Methods And Systems For Controlling Blood Pressure By Controlling Atrial Pressure

ABSTRACT

Systems and methods for controlling blood pressure by controlling atrial pressure and atrial stretch are disclosed. In some embodiments, a stimulation circuit may be configured to deliver a stimulation pulse to at least one cardiac chamber of a heart of a patient, and at least one controller may be configured to execute delivery of one or more stimulation patterns of stimulation pulses to the at least one cardiac chamber, wherein at least one of the stimulation pulses stimulates the heart such that an atrial pressure resulting from atrial contraction of an atrium overlaps in time a passive pressure build-up of the atrium, such that an atrial pressure of the atrium resulting from the stimulation is a combination of the atrial pressure resulting from atrial contraction and the passive pressure build-up and is higher than an atrial pressure of the atrium would be without the stimulation, and such that the blood pressure of the patient is reduced.

This application is a continuation of U.S. application Ser. No.15/372,603, filed Dec. 8, 2016 (U.S. Publication No. US2017/0080235,published Mar. 23, 2017), which is a continuation of U.S. applicationSer. No. 14/667,931, filed Mar. 25, 2015, now U.S. Pat. No. 9,526,900,issued Dec. 27, 2016, which is a division of U.S. application Ser. No.14/427,478, filed Mar. 11, 2015, now U.S. Pat. No. 9,370,662, issuedJun. 21, 2016, which is a National Stage of International ApplicationNo. PCT/US2014/042777, filed Jun. 17, 2014, which claims the priority ofInternational Application No. PCT/US2013/076600, filed Dec. 19, 2013,which claims the priority of U.S. application Ser. No. 13/826,215, filedMar. 14, 2013, now U.S. Pat. No. 9,008,769, issued Apr. 14, 2015, thepreceding two of which claim the benefit of U.S. Provisional ApplicationNo. 61/740,977, filed Dec. 21, 2012, and all of which are hereinincorporated by reference in their entirety.

BACKGROUND OF THE INVENTION 1. Field of the Invention

Embodiments of the present invention relate to the field of treatinghypertension through controlling cardiac functions, including fillingand contractions. Specific embodiments include application of focal,electrical stimulation to the heart.

2. Description of Related Art

Variations in blood pressure are known to occur normally, due forexample to increased activity (which normally elevates blood pressure)or significant blood loss (which tends to cause a reduction in bloodpressure). Blood pressure is however normally maintained within alimited range due for example to the body's baroreflex, whereby elevatedor decreased blood pressure affects cardiac function and thecharacteristics of the cardiovascular system by a feedback loop. Suchfeedback control is mediated by the nervous system as well as by theendocrine system (e.g., by natriuretic peptide). In hypertensiveindividuals, while baroreflex does function, blood pressure ismaintained at an elevated level.

Hypertension, or high blood pressure (e.g., blood pressure of 140/90mmHg or higher), is a serious health problem affecting many people. Forexample, approximately 74.5 million people aged 20 years and older andliving in the United States have high blood pressure. Hypertension maylead to such life-threatening conditions as stroke, heart attack, and/orcongestive heart failure. Approximately 44.1% of people with high bloodpressure and under current treatment have satisfactory control of theirhypertension. Correspondingly, 55.9% of the same people have poorcontrol. Traditionally, treatment for hypertension has includedmedication and lifestyle changes. These two types of treatment are noteffective for all patients. Additionally, side effects may preventcertain patients from taking medication. Accordingly, there remains aneed for additional techniques for lowering blood pressure.

SUMMARY OF THE INVENTION

Methods and devices for reducing blood pressure are disclosed. Someembodiments treat hypertension mechanically instead of or in addition totreating hypertension pharmaceutically. In some embodiments, anelectrical stimulator, such as a pacemaker or other type of devicehaving a pulse generator, may be used to stimulate a patient's heart toreduce blood pressure. When the heart is stimulated in a consistent wayto reduce blood pressure, the cardiovascular system may adapt to thestimulation over time and revert to a higher blood pressure. Therefore,in some embodiments, the stimulation pattern may be configured to beable to modulate the baroreflex such that the adaptation response of thecardiovascular system is reduced or even prevented.

In some embodiments, an electrical stimulator may be used to stimulate apatient's heart to cause at least a portion of an atrial contraction tooccur while the atrioventricular valve is closed. Such an atrialcontraction may deposit less blood into the corresponding ventricle thanwhen the atrioventricular valve is opened during an atrial contraction,which may cause a practically immediate drop in blood pressure.

In some embodiments, an electrical stimulator may be used to stimulate apatient's heart such that an atrial pressure resulting from atrialcontraction of an atrium overlaps in time a passive pressure build-up ofthe atrium, thereby providing an atrial pressure of the atrium that is acombination of the atrial pressure resulting from atrial contraction andthe passive pressure build-up and is higher than an atrial pressure ofthe atrium would be without the stimulation. This may cause an increasein atrial stretch thereby reducing blood pressure through hormonaland/or neuronal pathways. This reduction in blood pressure may take sometime to manifest, and its timeline would depend on the hormonal and/orneuronal pathways. The atrial pressure resulting from atrial contractionmay culminate in a maximum atrial pressure resulting from atrialcontraction. The passive pressure build-up of the atrium may culminatein a maximum passive pressure build-up of the atrium. Alternatively oradditionally, overlapping in time an atrial pressure resulting fromatrial contraction of an atrium and a passive pressure build-up of theatrium may include overlapping in time the maximum atrial pressureresulting from atrial contraction and the maximum passive pressurebuild-up. In some embodiments, overlapping the aforementioned maxima mayresult in a combined atrial pressure (of the atrial pressure resultingfrom atrial contraction and the passive pressure build-up) that ishigher than an atrial pressure of the atrium would be without thestimulation.

In some embodiments, the electrical stimulator may be used to stimulatea patient's heart to cause within a single cardiac cycle at least aportion of an atrial contraction to occur while the atrioventricularvalve is closed and/or to stimulate a patient's heart such that anatrial pressure resulting from atrial contraction of an atrium overlapsin time a passive pressure build-up of the atrium, thereby providing anatrial pressure of the atrium that is a combination of the atrialpressure resulting from atrial contraction and the passive pressurebuild-up and is higher than an atrial pressure of the atrium would bewithout the stimulation.

Some embodiments may use artificial valves in treating hypertension. Insome medical conditions, where one or more of the atrioventricular (AV)valves malfunctions, the valve(s) may be replaced by implantation ofartificial (prosthetic) valve(s). These artificial valves may benormally configured to passively open and close, as do natural valves,as a function of pressure differences between the atria and ventricles.Passive artificial valves are normally classified in three types basedon their mechanical structure: caged ball valves, tilting disc valves,and bi-leaflet valves. As an alternative, some embodiments may use anactive artificial valve that is configured to actively open and close.

In one aspect, an embodiment provides a system for reducing bloodpressure in a patient having a pretreatment blood pressure. The systemmay comprise at least one stimulation electrode for stimulating at leastone chamber of a heart of a patient with a stimulating pulse. The systemmay comprise at least one controller configured to execute a stimulationpattern of stimulating pulses to at least a chamber of the heart. Thestimulation pattern may include a first stimulation setting and a secondstimulation setting different from the first stimulation setting. Atleast one of the first stimulation setting and the second stimulationsetting may be configured to reduce or prevent atrial kick and/or tocontrol atrial pressure and/or stretch.

In one aspect, an embodiment provides a system for reducing bloodpressure. The system may comprise at least one stimulation electrode forstimulating at least one chamber of a heart of a patient. The system mayinclude at least one controller configured to execute a stimulationpattern comprising multiple stimulation pulses. At least one stimulationpulse of the multiple stimulation pulses may have a first stimulationsetting configured to reduce atrial kick in at least one ventricle. Atleast one stimulation pulse of the multiple stimulation pulses may havea second stimulation setting configured to reduce the baroreflexresponse to the reduction in atrial kick such that the increase in bloodpressure values occurring between stimulation pulses is limited to apredetermined value or range of values.

In another aspect, an embodiment provides a device for reducing bloodpressure of a patient having a pretreatment blood pressure and apretreatment ventricular filling volume. The device may comprise astimulation circuit configured to deliver a stimulation pulse to atleast one of an atrium and a ventricle. The device may comprise aprocessor circuit coupled to the stimulation circuit and optionally alsoto a sensing circuit.

In some embodiments, the device processor circuit may be configured tooperate in an operating mode in which the device controls the AV delay,which, as used herein, may be taken to mean a delay occurring in asingle heartbeat between ventricle excitation and/or contraction andatrial excitation and/or contraction. In addition, as used herein, theAV delay in a system or method may be taken to mean, within oneheartbeat, a time delay between delivery of at least one excitatorystimulus to a ventricle and one of: the sensing of an onset of atrialexcitation; the timing of an anticipated onset of atrial excitation; andthe delivery of at least one excitatory stimulus to the atrium.

This AV delay may be set by delivering at least one stimulation pulse toboth of at least one atrium and at least one ventricle. Optionally thisstimulation is performed at a rate that is higher than the naturalactivity of the heart. Such rate may, for example, be set using at leastone sensing electrode to sense the natural activity in the heart (e.g.,in the right atrium when stimulation is not delivered) and adjusting thestimulation pulse delivery rate accordingly.

Optionally, when ventricular excitation is timed to commence before thedelivery of one or more stimulation pulses to the atria, the delivery ofstimulation pulses to the heart is timed such that one or moreexcitatory pulses are delivered to an atrium at a time that is earlierthan the next anticipated natural onset of atrial excitation.

In some embodiments, the AV delay may be set by delivering at least onestimulation pulse to one or more ventricles but not to the atria. Insuch case, the natural activity of one or more of the atria may besensed and the timing of ventricle excitation and/or contraction may beset to precede its natural expected timing based on the sensed atrialactivity rate.

In some embodiments, the processor circuit may be configured to operatein an operating mode in which a ventricle is stimulated to causeventricular excitation to commence between about 0 milliseconds (ms) andabout 50 ms before the onset of atrial excitation in at least oneatrium, thereby reducing the ventricular filling volume from thepretreatment ventricular filling volume and reducing the patient's bloodpressure from the pretreatment blood pressure. In such embodiments,atrial excitation may be sensed to determine the onset of atrialexcitation. For example, the processor circuit may be configured tooperate in an operating mode in which one or more excitatory pulses aredelivered to a ventricle between about 0 ms and about 50 ms before anext atrial excitation is anticipated to take place. The time intervalbetween the onset of atrial excitation and the moment that atrialexcitation is sensed may be known or estimated, and used to calculatethe timing of an onset of atrial excitation. For example, if it is knownor estimated that atrial excitation is sensed 5 ms after the onset ofatrial excitation and the ventricle is to be stimulated 20 ms before theonset of atrial excitation, then the ventricle is to be stimulated 25 msbefore the next anticipated sensing of atrial excitation. In otherembodiments, the processor circuit may be configured to operate in anoperating mode in which an atrium is stimulated to cause atrialexcitation to commence between about 0 ms and about 50 ms after theonset of ventricular excitation in at least one ventricle, therebyreducing the ventricular filling volume from the pretreatmentventricular filling volume and reducing the patient's blood pressurefrom the pretreatment blood pressure. For example, the processor circuitmay be configured to operate in an operating mode in which one or moreexcitatory pulses are delivered to an atrium between about 0 ms andabout 50 ms after one or more excitatory pulses are provided to thepatient's ventricle. In such embodiments, the pacing may be timedwithout relying on sensing atrial excitation. Optionally, in suchembodiments, atrial excitation is sensed in order to confirm that one ormore excitatory pulses are delivered to an atrium before a naturalexcitation takes place. Optionally, atrial excitation is set to commencebetween about 0 ms and about 50 ms after the onset of ventricularexcitation when the intrinsic atrial excitation rate is lower than theintrinsic ventricular excitation rate.

In some embodiments, the timing of the mechanical contraction inrelation to electrical excitation of a chamber for a patient may bedetermined, for example, by sensing changes in atrial and ventricularpressures, sensing wall motion using ultrasound (e.g., echocardiographyor cardiac echo), changes in impedance, or the opening and/or closing ofa cardiac valve, using implanted and/or external sensors as known in theart. Examples for such sensors include pressure sensors, impedance,ultrasound sensors, and/or one or more audio sensors and/or one or moreblood flow sensors.

The timing of the mechanical contraction in relation to electricalexcitation of a chamber for a patient may be taken into account and theprocessor circuit may be configured accordingly, such that the one ormore excitatory pulses are delivered to the heart in a timing that willgenerate a desired pattern of contraction. This may be performed in aclosed loop mode, using one or more implanted sensors, and/or may beperformed occasionally (e.g., on implantation of a device and/or duringa checkup), for example, using an interface with an external measurementdevice.

The operating mode may include stimulating the ventricle to cause theventricle to commence contraction before the onset of contraction of theat least one atrium.

The operating mode may include stimulating the ventricle to cause theventricle to commence contraction before the end of contraction of theat least one atrium, thereby causing the AV valve to be closed during atleast part of a contraction of the at least one atrium.

The operating mode may include stimulating the ventricle to cause theventricle to commence contraction within less than 100 ms after theonset of contraction of the at least one atrium.

Optionally, care is taken to ensure that atrial contraction willcommence before ventricle contraction has reached peak pressure. This ispossible even in cases in which ventricular contraction will havecommenced before the onset of atrial contraction, as atrial contractionis typically faster than ventricular contraction. Accordingly, one ofthe following settings may be selected:

-   -   a. The operating mode may include stimulating the ventricle to        cause the ventricle to commence contraction at any time during        atrial contraction but before the atrium reaches its maximal        pressure that is due to the atrial contraction.    -   b. The operating mode may include stimulating the ventricle to        cause the ventricle to commence contraction at any time during        atrial contraction but after the atrium reaches its maximal        pressure that is due to the atrial contraction.    -   c. The operating mode may include stimulating the ventricle at        such timing that contraction would commence in both the atrium        and ventricle at essentially the same time (e.g., with no more        than 5 ms from one another).    -   d. The operating mode may include stimulating the ventricle to        cause the ventricle to commence contraction at such timing that        the peak of atrial contraction would occur when the ventricle is        near or at maximal stretch, thus causing an increase in the        stretch of the atrial wall, described in more detail below        relative to the isovolumic phase and rapid ejection phase of the        ventricle.

The operating mode may include stimulating the ventricle to cause theventricle to contract at least partially before the onset of contractionof the at least one atrium, thereby causing the AV valve to be closedduring the onset of contraction of the at least one atrium.

Optionally, the processor circuit may be configured to operate in anoperating mode in which one or more excitatory pulses are delivered toan atrium between about 0 ms and about 50 ms after one or moreexcitatory pulses are delivered to the patient's ventricle.

In another aspect, an embodiment provides a method for reducing bloodpressure of a patient having a pretreatment blood pressure and apretreatment ventricular filling volume. The method may comprisedelivering a stimulation pulse from a stimulation circuit to at leastone of an atrium and a ventricle, and operating a processor circuitcoupled to the stimulation circuit to operate in an operating mode inwhich a ventricle is stimulated to cause ventricular excitation tocommence between about 0 ms and about 50 ms before the onset of atrialexcitation in at least one atrium, thereby reducing the ventricularfilling volume from the pretreatment ventricular filling volume andreducing the patient's blood pressure from the pretreatment bloodpressure. In such embodiments, atrial excitation may be sensed todetermine the onset of atrial excitation. For example, the method mayinclude delivering one or more excitatory pulses to a ventricle betweenabout 0 ms and about 50 ms before a next atrial excitation isanticipated to take place. The time interval between the onset of atrialexcitation and the moment that atrial excitation is sensed may be knownand used to calculate the timing of the onset of atrial excitation. Forexample, if it is known or estimated that atrial excitation is sensed 5ms after the onset of atrial excitation and the ventricle is to bestimulated 20 ms before the onset of atrial excitation, then theventricle is to be stimulated 25 ms before the next anticipated sensingof atrial excitation. In other embodiments, the method may compriseoperating a processor circuit coupled to the stimulation circuit tooperate in an operating mode in which an atrium is stimulated to causeatrial excitation to commence between about 0 ms and about 50 ms afterthe onset of ventricular excitation in at least one ventricle, therebyreducing the ventricular filling volume from the pretreatmentventricular filling volume and reducing the patient's blood pressurefrom the pretreatment blood pressure. For example, the method mayinclude delivering one or more excitatory pulses to an atrium betweenabout 0 ms and about 50 ms after delivering one or more excitatorypulses to the patient's ventricle. In such embodiments, the pacing maybe timed without relying on sensing atrial excitation. Optionally, suchembodiments comprise sensing atrial excitation in order to confirm thatone or more excitatory pulses are delivered to an atrium before anatural excitation takes place. Optionally, atrial excitation is set tocommence between about 0 ms and about 50 ms after the onset ofventricular excitation when the intrinsic atrial excitation rate islower than the intrinsic ventricular excitation rate.

In some embodiments, the timing of the mechanical contraction inrelation to electrical excitation of a chamber for a patient may beevaluated using, for example, ultrasound (e.g., echocardiography orcardiac echo) or other known means. The timing of the mechanicalcontraction in relation to electrical excitation of a chamber for apatient may be taken into account and the timing of the delivery of theone or more excitatory pulses to the heart may be selected so as togenerate a desired pattern of contraction.

The operating mode may include stimulating the ventricle to cause theventricle to contract before the onset of contraction of the at leastone atrium.

The operating mode may include stimulating the ventricle to cause theventricle to contract before the onset of contraction of the at leastone atrium, thereby causing the AV valve to be closed during at leastpart of a contraction of the at least one atrium.

The operating mode may include stimulating the ventricle to cause theventricle to contract before the end of contraction of the at least oneatrium, thereby causing the AV valve to be closed during the onset ofcontraction of at least atrium.

Optionally, the method comprises delivering one or more excitatorypulses to an atrium between about 0 ms and about 50 ms after deliveringone or more excitatory pulses to the patient's ventricle.

In another aspect, an embodiment provides a device for reducing bloodpressure of a patient having a pretreatment blood pressure and apretreatment ventricular filling volume. The device may comprise astimulation circuit configured to deliver a stimulation pulse to atleast one cardiac chamber of a patient's heart. The device may comprisea processor circuit coupled to the stimulation circuit. The processorcircuit may be configured to operate in an operating mode in which atleast one cardiac chamber is stimulated to cause between about 40% of anatrial contraction and about 100% of an atrial contraction to occur at atime when an atrioventricular valve related to the atrium is closed,thereby reducing the ventricular filling volume from the pretreatmentventricular filling volume and reducing the patient's blood pressurefrom the pretreatment blood pressure. This can be achieved, for example,by causing the atrium to commence contraction about 60 ms or less beforethe closure of the AV valve. Optionally, this timing may be setperiodically (e.g., upon implantation) based on data from an externalsensor and/or as a closed loop using one or more implanted sensors.

In another aspect, an embodiment provides a device for reducing bloodpressure of a patient having a pretreatment blood pressure and apretreatment ventricular filling volume. The device may comprise astimulation circuit configured to deliver a stimulation pulse to atleast one cardiac chamber. The device may comprise a processor circuitcoupled to the stimulation circuit. The processor circuit may beconfigured to operate in an operating mode in which at least one cardiacchamber is paced to cause about 50% to about 95% of an atrialcontraction to occur during ventricular systole, thereby reducing theventricular filling volume from the pretreatment ventricular fillingvolume and reducing the patient's blood pressure from the pretreatmentblood pressure. This can be achieved, for example, by causing the atriumto commence contraction about 50 ms to 5 ms before commencement ofventricular contraction. Optionally, the timing of commencement ofventricular contraction may be set according to the timing of closure ofan AV valve. Optionally, this timing may be set periodically (e.g., uponimplantation) based on data from an external sensor and/or as a closedloop using one or more implanted sensors.

In another aspect, an embodiment provides a method, carried out with animplanted heart muscle stimulator associated with a heart of a patient,for treating a blood pressure disorder in the patient, the patienthaving a pretreatment blood pressure. The method may comprisestimulating a heart to cause an atrium thereof to contract while a heartvalve associated with the atrium is closed such that the contractiondistends the atrium, and the distending atrium results in reducing thepatient's blood pressure from the pretreatment blood pressure. This canbe achieved, for example, by causing the atria to contract at a timewhen the pressure in the ventricle is maximal so that the active forceof atrial contraction will increase atrial pressure and atrial stretchabove the maximal passive pressure and stretch caused by the contractionof the associated ventricle(s). In such cases, the timing of the maximalcontraction of the atria should coincide with the end of the isovolumicperiod or during the rapid ejection period of the ventricle. Optionally,this timing may be set periodically (e.g., upon implantation) based ondata from an external sensor and/or as a closed loop using one or moreimplanted sensors.

In another aspect, an embodiment provides a system for reducing bloodpressure in a patient by controlling atrial pressure and atrial stretch.The system may include a stimulation circuit configured to deliver astimulation pulse to at least one cardiac chamber of a heart of thepatient, and at least one controller configured to execute the deliveryof one or more stimulation patterns of stimulation pulses to the atleast one cardiac chamber. The at least one of the stimulation pulsesmay stimulate the heart such that an atrial pressure resulting fromatrial contraction of an atrium overlaps in time a passive pressurebuild-up of the atrium, such that an atrial pressure of the atriumresulting from the stimulation is a combination of the atrial pressureresulting from atrial contraction and the passive pressure build-up andis higher than an atrial pressure of the atrium would be without thestimulation, and such that the blood pressure of the patient is reduced.

The atrial pressure of the atrium resulting from the stimulation maycause an increased atrial stretch of the atrium that reduces bloodpressure through hormonal and/or neural pathways.

The atrial pressure resulting from atrial contraction may culminate in amaximum atrial pressure resulting from atrial contraction. The passivepressure build-up of the atrium may culminate in a maximum passivepressure build-up of the atrium. Alternatively or additionally,overlapping in time an atrial pressure resulting from atrial contractionof an atrium and a passive pressure build-up of the atrium may includeoverlapping in time both a maximum atrial pressure resulting from atrialcontraction and a maximum passive pressure build-up. In someembodiments, overlapping the aforementioned maxima may result in acombined atrial pressure (of the atrial pressure resulting from atrialcontraction and the passive pressure build-up) that is higher than anatrial pressure of the atrium would be without the stimulation.

The at least one of the stimulation pulses may include stimulating theatrium of the heart. The at least one of the stimulation pulses mayinclude stimulating a ventricle of the heart. The at least one of thestimulation pulses may also include pacing the atrium and the ventricle,optionally at a substantially equal rate, or pacing the atrium at a ratehigher than a rate at which the ventricle is paced.

The at least one of the stimulation pulses may include stimulating theatrium such that the atrium contracts twice during a single cardiaccycle, for example, either by stimulation the atrium twice during asingle cardiac cycle or by stimulation the atrium once during a singlecardiac cycle.

Optionally, the at least one of the stimulation pulses may includestimulating the atrium such that the atrium contracts only once during asingle cardiac cycle.

The at least one of the stimulation pulses may also include stimulatingthe heart such that atrial kick is reduced or prevented.

The one or more stimulation patterns may also include stimulating theheart such that atrial kick is reduced or prevented. The at least one ofthe stimulation patterns may include stimulating the heart at aplurality of heartbeats, wherein at least some of the stimulation pulsesstimulate the heart such that an atrial pressure resulting from atrialcontraction of an atrium overlaps in time a passive pressure build-up ofthe atrium, such that an atrial pressure of the atrium resulting fromthe stimulation is a combination of the atrial pressure resulting fromatrial contraction and the passive pressure build-up and is higher thanan atrial pressure of the atrium would be without the stimulation, andwherein at least some of the stimulation pulses are configured to reduceor prevent atrial kick.

A stimulation pulse may be provided such that in a single heartbeat bothatrial kick is reduced or prevented and an atrial pressure resultingfrom atrial contraction of an atrium overlaps in time the passivepressure build-up of the atrium such that an atrial pressure of theatrium resulting from the stimulation is a combination of the atrialpressure resulting from atrial contraction and the passive pressurebuild-up and is higher than an atrial pressure of the atrium would bewithout the stimulation.

The at least one stimulation pattern may include at least onestimulation pulse set to have in a single heartbeat a first atrialcontraction to commence when an atrioventricular valve is open and endafter the atrioventricular valve is closed, and to elicit a secondatrial contraction in which an atrial pressure resulting from atrialcontraction of an atrium overlaps in time a passive pressure build-up ofthe atrium, such that an atrial pressure of the atrium resulting fromthe stimulation is a combination of the atrial pressure resulting fromatrial contraction and the passive pressure build-up and is higher thanan atrial pressure of the atrium would be without the stimulation. Thefirst atrial contraction may be sensed and the second atrial contractionmay be paced. Alternatively, the first atrial contraction and the secondatrial contraction may be paced.

Alternatively, the at least one stimulation pattern may include at leastone stimulation pulse set to have in a single heartbeat a first atrialcontraction to commence when an atrioventricular valve is open and endbefore the atrioventricular valve is closed, and to elicit a secondatrial contraction in which an atrial pressure resulting from atrialcontraction of an atrium overlaps in time the passive pressure build-upof the atrium, such that an atrial pressure of the atrium resulting fromthe stimulation is a combination of the atrial pressure resulting fromatrial contraction and the passive pressure build-up and is higher thanan atrial pressure of the atrium would be without the stimulation. Thefirst atrial contraction may be sensed and the second atrial contractionmay be paced. Alternatively, the first atrial contraction and the secondatrial contraction may be paced.

The one or more stimulation patterns may include alternating between aplurality of stimulation patterns having a different ratio of: (1) firststimulation pulses that stimulate the heart such that an atrial pressureresulting from atrial contraction of an atrium overlaps in time apassive pressure build-up of the atrium, such that an atrial pressure ofthe atrium resulting from the stimulation is a combination of the atrialpressure resulting from atrial contraction and the passive pressurebuild-up and is higher than an atrial pressure of the atrium would bewithout the stimulation; and (2) second stimulation pulses thatstimulate the heart such that atrial kick is reduced or prevented.Optionally, the one or more stimulation patterns may include at leastone stimulation pulse configured to reduce or prevent atrial kick andstimulate the heart such that an atrial pressure resulting from atrialcontraction of an atrium overlaps in time a passive pressure build-up ofthe atrium, such that an atrial pressure of the atrium resulting fromthe stimulation is a combination of the atrial pressure resulting fromatrial contraction and the passive pressure build-up and is higher thanan atrial pressure of the atrium would be without the stimulation, bothin a single cardiac cycle.

The one or more stimulation patterns may include alternating between aplurality of stimulation patterns having a different ratio of: (1) firststimulation pulses that stimulate the heart such that an atrial pressureresulting from atrial contraction of an atrium overlaps in time apassive pressure build-up of the atrium, such that an atrial pressure ofthe atrium resulting from the stimulation is a combination of the atrialpressure resulting from atrial contraction and the passive pressurebuild-up and is higher than an atrial pressure of the atrium would bewithout the stimulation; and (2) second stimulation pulses that do notprovide an atrial pressure resulting from atrial contraction of anatrium that overlaps in time a passive pressure build-up of the atrium.

The at least one stimulation pulse may include pacing at least one ofthe atrium of the heart and a ventricle of the heart such that arelative timings of excitation corresponds to an atrioventricular delayof approximately 2 ms.

The at least one stimulation pulse may include pacing at least one ofthe atrium of the heart and a ventricle of the heart such that arelative timing of excitation corresponds to an atrioventricular delayof between approximately 30 ms and approximately 0 ms, or even between10 ms and 0 ms.

In another aspect, an embodiment provides a method for reducing bloodpressure of a patient by controlling atrial pressure and atrial stretch.The method may be carried out with an implanted heart muscle stimulatorassociated with a heart of the patient. The method may includestimulating the heart to provide an atrial pressure resulting fromatrial contraction that overlaps in time a passive pressure build-up ofthe atrium, such that the overlapping atrial pressure resulting from theatrial contraction and passive pressure build-up elicits an atrialpressure that is a combination of the atrial pressure resulting fromatrial contraction and the passive pressure build-up and is higher thanan atrial pressure of the atrium would be without the stimulation, andsuch that the blood pressure of the patient is reduced.

The atrial pressure of the atrium resulting from the stimulation maycause an increased atrial stretch of the atrium that reduces bloodpressure through hormonal or neuronal pathways.

The atrial pressure resulting from atrial contraction may culminate in amaximum atrial pressure resulting from atrial contraction. The passivepressure build-up of the atrium may culminate in a maximum passivepressure build-up of the atrium. Alternatively or additionally,overlapping in time an atrial pressure resulting from atrial contractionof an atrium and a passive pressure build-up of the atrium may includeoverlapping in time both a maximum atrial pressure resulting from atrialcontraction and a maximum passive pressure build-up. In someembodiments, overlapping the aforementioned maxima may result in acombined atrial pressure (of the atrial pressure resulting from atrialcontraction and the passive pressure build-up) that is higher than anatrial pressure of the atrium would be without the stimulation. Themethod may therefore include stimulating the heart such that a maximumof atrial pressure resulting from atrial contraction of an atriumoverlaps in time a maximum passive pressure build-up of the atrium.

The method may include stimulating the atrium of the heart. The methodmay include additionally or alternatively stimulating a ventricle of theheart. The method may also include pacing the atrium and the ventricleat a substantially equal rate, or pacing the atrium at a rate higherthan a rate at which the ventricle is paced or contracts.

The method may further include stimulating the atrium such that theatrium contracts twice during a single cardiac cycle, for example,either by stimulating the atrium twice during a single cardiac cycle orby stimulating the atrium once during a single cardiac cycle.

Optionally, the method may include stimulating the atrium such that theatrium contracts only once during a single cardiac cycle.

The method may also include stimulating the heart such that atrial kickis reduced or prevented. Stimulating the heart may include delivering astimulation pattern to the heart at a plurality of heartbeats, whereinat least some of the stimulation pulses in the stimulation patternstimulate the heart such that an atrial pressure resulting from atrialcontraction of an atrium overlaps in time a passive pressure build-up ofthe atrium, such that an atrial pressure of the atrium resulting fromthe stimulation is a combination of the atrial pressure resulting fromatrial contraction and the passive pressure build-up and is higher thanan atrial pressure of the atrium would be without the stimulation, andwherein at least some of the stimulation pulses are configured to reduceor prevent atrial kick. A stimulation pulse may be provided such that ina single heartbeat both atrial kick is reduced or prevented and anatrial pressure resulting from atrial contraction of an atrium overlapsin time the passive pressure build-up of the atrium such that an atrialpressure of the atrium resulting from the stimulation is a combinationof the atrial pressure resulting from atrial contraction and the passivepressure build-up and is higher than an atrial pressure of the atriumwould be without the stimulation.

Stimulating the heart may include delivering at least one stimulationpulse set to have in a single heartbeat a first atrial contraction tocommence when an atrioventricular valve is open and end after theatrioventricular valve is closed, and to elicit a second atrialcontraction in which an atrial pressure resulting from atrialcontraction of an atrium overlaps in time a passive pressure build-up ofthe atrium, such that an atrial pressure of the atrium resulting fromthe stimulation is a combination of the atrial pressure resulting fromatrial contraction and the passive pressure build-up and is higher thanan atrial pressure of the atrium would be without the stimulation. Thefirst atrial contraction may be sensed and the second atrial contractionmay be paced. Alternatively, the first atrial contraction and the secondatrial contraction may be paced.

Alternatively, stimulating the heart may include delivering at least onestimulation pulse set to have in a single heartbeat a first atrialcontraction to commence when an atrioventricular valve is open and endbefore the atrioventricular valve is closed, and to elicit a secondatrial contraction in which an atrial pressure resulting from atrialcontraction of an atrium overlaps in time the passive pressure build-upof the atrium, such that an atrial pressure of the atrium resulting fromthe stimulation is a combination of the atrial pressure resulting fromatrial contraction and the passive pressure build-up and is higher thanan atrial pressure of the atrium would be without the stimulation. Thefirst atrial contraction may be sensed and the second atrial contractionmay be paced. Alternatively, the first atrial contraction and the secondatrial contraction may be paced.

The method may further include alternating between a plurality ofstimulation patterns having a different ratio of: (1) first stimulationpulses that stimulate the heart such that an atrial pressure resultingfrom atrial contraction of an atrium overlaps in time a passive pressurebuild-up of the atrium, such that an atrial pressure of the atriumresulting from the stimulation is a combination of the atrial pressureresulting from atrial contraction and the passive pressure build-up andis higher than an atrial pressure of the atrium would be without thestimulation; and (2) second stimulation pulses that stimulate the heartsuch that atrial kick is reduced or prevented. Optionally, the one ormore stimulation patterns may include at least one stimulation pulseconfigured to reduce or prevent atrial kick and stimulate the heart suchthat an atrial pressure resulting from atrial contraction of an atriumoverlaps in time a passive pressure build-up of the atrium, such that anatrial pressure of the atrium resulting from the stimulation is acombination of the atrial pressure resulting from atrial contraction andthe passive pressure build-up and is higher than an atrial pressure ofthe atrium would be without the stimulation, both in a single cardiaccycle.

The method may further include alternating between a plurality ofstimulation patterns having a different ratio of: (1) first stimulationpulses that stimulate the heart such that an atrial pressure resultingfrom atrial contraction of an atrium overlaps in time a passive pressurebuild-up of the atrium, such that an atrial pressure of the atriumresulting from the stimulation is a combination of the atrial pressureresulting from atrial contraction and the passive pressure build-up andis higher than an atrial pressure of the atrium would be without thestimulation; and (2) second stimulation pulses that do not provide anatrial pressure resulting from atrial contraction of an atrium thatoverlaps in time a passive pressure build-up of the atrium.

The method may further include pacing at least one of the atrium of theheart and a ventricle of the heart such that a relative timing ofexcitation corresponds to an atrioventricular delay of approximately 2ms.

The method may further include pacing at least one of the atrium of theheart and a ventricle of the heart such that a relative timing ofexcitation corresponds to an atrioventricular delay of betweenapproximately 30 ms and approximately 0 ms.

In another aspect, an embodiment provides a method for reducing bloodpressure of a patient, which may be carried out with an implanted heartmuscle stimulator associated with a heart of the patient. The method mayinclude delivering one or more stimulation patterns of stimulationpulses to at least one cardiac chamber of the heart of the patient. Atleast one of the stimulation pulses may have a first stimulation settingand at least one of the stimulation pulses may have a second stimulationsetting different from the first stimulation setting. At least one ofthe first stimulation setting and the second stimulation setting may beconfigured to reduce or prevent atrial kick. Stimulation pulses having astimulation setting configured to reduce or prevent atrial kick may bedelivered based upon need.

Basing the delivery of stimulation pulses upon need may include one ormore of the following:

-   -   a. Limiting the treatment to a time of need, for example,        limiting the delivery of a stimulation setting configured to        reduce or prevent atrial kick to a time when a patient's blood        pressure is known to be or is expected to be abnormally high.        This may include using real time feedback measurements of one or        more blood pressure related parameters or basing an expected        pattern of need on previous measurements taken from the same        patient. For example, in some patients BP can be high 24 hours        per day, while other patients may experience high BP only during        a part of a 24-hour period (e.g., daytime or nighttime).    -   b. Preventing treatment when high BP is needed, for example,        preventing the delivery of a stimulation setting configured to        reduce or prevent atrial kick at such times as an increase in BP        may be a healthy and thus a desired condition. For example, BP        is known to increase when one is active and to reduce again when        activity is reduced (e.g., when exercising or performing a        physical task that is naturally associated with an increase in        BP).

Stimulation pulses having a stimulation setting configured to reduce orprevent atrial kick may be provided only during part of a 24-hourperiod, which may be a night or part thereof, or may be a day or partthereof.

Stimulation pulses having a stimulation setting configured to reduce orprevent atrial kick may be provided only when heart rate is below apredefined threshold. The predefined threshold may be an absolute value,such as 90 bpm. The predefined threshold may be set at a value relativeto the patient's average heart rate. For example, the predefinedthreshold may be at least one of 30 beats above average heart rate andabove the 80^(th) percentile of the heart rate.

Stimulation pulses having a stimulation setting configured to reduce orprevent atrial kick may be provided only when the patient is at rest orat an activity level below a defined threshold. The method may furtherinclude determining whether the patient is at rest or at an activitylevel below a defined threshold by sensing at least one of motion,posture, respiration rate, and heart rate.

Optionally, the patient may be deemed to be “at rest” or “at a lowactivity level” when the patient's activity is low. For example, as longas the heart rate does not exceed a predefined threshold or only lowactivity is sensed (characterized, for example, by mild and/or slowmotion and/or low rate of posture change and/or no significant increasein respiration, etc.), a patient may be considered “at rest” or “at alow activity level.” For example, sitting activity such as while readingor talking, or motion around the house or at an office, may be deemed tobe a sufficiently low activity level as to allow the delivery ofstimulation pulses having a stimulation setting configured to reduce orprevent atrial kick.

The one or more stimulation patterns may be selected based on a measuredblood pressure parameter. The method may further include changing theone or more stimulation patterns when baroreflex is sensed.

In another aspect, an embodiment provides a system for reducing bloodpressure of a patient including a stimulation circuit configured todeliver one or more stimulation patterns of stimulation pulses to atleast one cardiac chamber of the heart of the patient, and at least onecontroller configured to execute the delivery of the one or morestimulation patterns of stimulation pulses to the at least one cardiacchamber. At least one of the stimulation pulses may have a firststimulation setting and at least one of the stimulation pulses may havea second stimulation setting different from the first stimulationsetting. At least one of the first stimulation setting and the secondstimulation setting may be configured to reduce or prevent atrial kick.Stimulation pulses having a stimulation setting configured to reduce orprevent atrial kick may be delivered based upon need.

The at least one controller may be configured to deliver the stimulationpulses having a stimulation setting configured to reduce or preventatrial kick, only during part of a 24-hour period. The part of a 24-hourperiod may be a night or part thereof, or may be a day or part thereof.

The at least one controller may be configured to deliver the stimulationpulses having a stimulation setting configured to reduce or preventatrial kick, only when heart rate is below a predefined threshold. Thepredefined threshold may be an absolute value, such as 90 bpm. Thepredefined threshold may be set at a value relative to the patient'saverage heart rate. For example, the predefined threshold may be atleast one of 30 beats above average heart rate and above the 80^(th)percentile of the heart rate.

The at least one controller may be configured to deliver the stimulationpulses having a stimulation setting configured to reduce or preventatrial kick, only when the patient is at rest or at a low activitylevel. The system may be configured to determine whether the patient isat rest or at a low activity level by sensing at least one of motion,posture, respiration rate, and heart rate.

The at least one controller may be configured to select the one or morestimulation patterns based on a measured blood pressure parameter. Theat least one controller may be configured to change the one or morestimulation patterns when baroreflex is sensed.

In another aspect, an embodiment may provide a method for adjusting apulse setting in a system for controlling blood pressure. The method mayinclude receiving atrial pressure data associated with an atrium of aheart of a patient during at least one cardiac cycle. The atrialpressure data may result from the system's delivering to the heart astimulation pulse having a first pulse setting. The method may furthercomprise analyzing the atrial pressure data, and providing an adjustedsecond pulse setting according to the analysis, with the adjusted secondpulse setting being different from the first pulse setting. Theanalyzing may include analyzing the atrial pressure data to estimate anoverlap in time between an atrial pressure resulting from atrialcontraction and a passive pressure build-up of the atrium. The analyzingmay further include analyzing the atrial pressure data to estimate anoverlap in time between a maximum atrial pressure resulting from atrialcontraction and a maximum passive pressure build-up of the atrium. Theanalyzing may include analyzing the atrial pressure data to compare afirst atrial pressure (or a maximal atrial pressure) attained in acardiac cycle where a stimulation pulse was delivered, to a secondatrial pressure of the atrium without the stimulation. The analyzing mayalso include plotting the atrial pressure data and/or mathematicallyanalyzing the atrial pressure data.

In another aspect, an embodiment may provide a system for reducing bloodpressure. The system may include means for providing information aboutpressure variation in an atrium during at least one cardiac cycle of aheart, means for generating stimulation pulses, and means for applyingthe stimulation pulses to at least one cardiac chamber. The means forgenerating stimulation pulses may be arranged to generate thestimulation pulses so as to control the timing of an atrial contractionrelative to the timing of a ventricular contraction in a single cardiaccycle according to the information about pressure variation in theatrium.

The information about pressure variation in an atrium may includeinformation about occurrence of an atrial contraction and/or informationabout occurrence of a ventricular contraction. The means for generatingstimulation pulses may be arranged for generating for at least onecardiac cycle: at least one atrial stimulation pulse for generating anatrial contraction; and/or at least one ventricular stimulation pulsefor generating a ventricular contraction. The means for generatingstimulating pulses may be arranged: for generating the at least oneatrial stimulation pulse, on the basis of the information about theoccurrence of the atrial contraction and/or the information about theoccurrence of the ventricular contraction, in a timed relationship tothe occurrence of the atrial contraction and/or to the occurrence of theventricular contraction; and/or for generating the at least oneventricular stimulation pulse on the basis of the information about theoccurrence of the ventricular contraction and/or the information aboutthe occurrence of the atrial contraction, in a timed relationship to theoccurrence of the ventricular contraction and/or to the occurrence ofthe atrial contraction. The information about the occurrence of theatrial contraction may include information about the occurrence of a Pwave pattern in the natural stimulation pattern of a cardiac cycle. Theinformation about the occurrence of the ventricular contraction mayinclude information about the occurrence of a QRS complex in the naturalstimulation pattern of a cardiac cycle.

In another aspect, an embodiment may provide a system for reducing bloodpressure. The system may include means for providing information abouttiming of one or more heart activity events, means for generatingstimulation pulses, and means for applying the stimulation pulses to atleast one cardiac chamber. The information about timing of one or moreheart activity events may include at least one of: occurrence of anatrial contraction of an atrium, occurrence of a ventricular contractionof a ventricle, opening of an atrioventricular valve, closure of anatrioventricular valve, electrical activity of the atria, electricalactivity of the ventricle, blood flow, atrial pressure of the atrium,changes in atrial pressure of the atrium, and heart rate. The means forgenerating stimulation pulses may be arranged to generate thestimulation pulses so as to set a timing of atrial contraction relativeto ventricular contraction based on the information.

The timing of atrial contraction relative to ventricular contraction maycorrespond to an AV delay within a range of about 30 ms to about 0 ms.The means for generating stimulation pulses may be arranged to generatethe stimulation pulses so as to: provide an excitatory stimulus to theatrium within a range of about 30 ms to about 0 ms before ventricularexcitation occurs; provide an excitatory stimulus to the ventriclewithin a range of about 30 ms to about 0 ms after atrial excitationoccurs; and/or provide an excitatory stimulus to the atrium and thenwithin a range of about 30 ms to about 0 ms later provide an excitatorystimulus to the ventricle.

The information about timing of one or more heart activity events mayinclude information about timing between two or more heart activityevents in a single cardiac cycle.

The means for generating stimulation pulses may be arranged forgenerating for at least one cardiac cycle: at least one atrialstimulation pulse for generating an atrial contraction; and/or at leastone ventricular stimulation pulse for generating a ventricularcontraction. The means for generating stimulating pulses may bearranged: for generating the at least one atrial stimulation pulse, onthe basis of the information about the occurrence of the atrialcontraction and/or the information about the occurrence of theventricular contraction, in a timed relationship to the occurrence ofthe atrial contraction and/or to the occurrence of the ventricularcontraction; and/or for generating the at least one ventricularstimulation pulse on the basis of the information about the occurrenceof the ventricular contraction and/or the information about theoccurrence of the atrial contraction, in a timed relationship to theoccurrence of the ventricular contraction and/or to the occurrence ofthe atrial contraction. The information about the occurrence of theatrial contraction may include information about the occurrence of a Pwave pattern in the natural stimulation pattern of a cardiac cycle. Theinformation about the occurrence of the ventricular contraction mayinclude information about the occurrence of a QRS complex in the naturalstimulation pattern of a cardiac cycle.

In another aspect, an embodiment provides another method for reducingblood pressure of a patient by controlling atrial pressure and atrialstretch. The method may be carried out with an implanted heart musclestimulator associated with a heart of the patient. The method mayinclude delivering one or more stimulation patterns of stimulationpulses to at least one cardiac chamber, wherein at least one of thestimulation pulses has a first stimulation setting and at least one ofthe stimulation pulses has a second stimulation setting different fromthe first stimulation setting, at least one of the first stimulationsetting and the second stimulation setting being configured to have anatrium contract such that an atrial pressure resulting from atrialcontraction of an atrium overlaps in time a passive pressure build-up ofthe atrium; and providing, through the overlapping atrial pressureresulting from atrial contraction and passive pressure build-up, anatrial pressure of the atrium that is a combination of the atrialpressure resulting from atrial contraction and the passive pressurebuild-up and is higher than an atrial pressure of the atrium would bewithout the stimulation, thereby causing increased atrial stretch of theatrium that reduces blood pressure through hormonal or neuronalpathways. Optionally, at least one of the first stimulation setting andthe second stimulation setting may be configured to have an atriumcontract such that a maximum atrial pressure resulting from atrialcontraction overlaps in time a maximum passive pressure build-up in theatrium, and the method may include providing, through the overlappingmaximum atrial pressure resulting from atrial contraction and maximumpassive pressure build-up, an atrial pressure of the atrium that ishigher than an atrial pressure of the atrium would be without thestimulation, thereby causing increased atrial stretch of the atrium thatreduces blood pressure through hormonal or neuronal pathways.

In another aspect, an embodiment provides a system for reducing bloodpressure of a patient by controlling atrial pressure and atrial stretch.The system may include a stimulation circuit configured to deliver oneor more stimulation patterns of stimulation pulses to at least onecardiac chamber, and at least one controller configured to executedelivery of one or more stimulation patterns of stimulation pulses to atleast one cardiac chamber. At least one of the stimulation pulses mayhave a first stimulation setting and at least one of the stimulationpulses may have a second stimulation setting different from the firststimulation setting. At least one of the first stimulation setting andthe second stimulation setting may be configured to have an atrium ofthe heart contract such that an atrial pressure resulting from atrialcontraction of an atrium overlaps in time a passive pressure build-up ofthe atrium, thereby providing an atrial pressure of the atrium that is acombination of the atrial pressure resulting from atrial contraction andthe passive pressure build-up and is higher than an atrial pressure ofthe atrium would be without the stimulation, thereby causing increasedatrial stretch of the atrium that reduces blood pressure throughhormonal or neuronal pathways. Optionally, at least one of the firststimulation setting and the second stimulation setting may be configuredto have an atrium of the heart contract such that a maximum atrialpressure resulting from atrial contraction overlaps in time a maximumpassive pressure build-up in the atrium, thereby providing an atrialpressure of the atrium that is higher than an atrial pressure of theatrium would be without the stimulation, and causing increased atrialstretch of the atrium that reduces blood pressure through hormonal orneuronal pathways.

In another aspect, an embodiment provides a method for treating a bloodpressure disorder in a patient by controlling atrial pressure and atrialstretch. The method may be carried out with an implanted heart musclestimulator associated with a heart of the patient, with the patienthaving a pretreatment blood pressure. The method may include stimulatingthe heart to have an atrium thereof contract while a heart valveassociated with the atrium is closed such that the contraction distendsthe atrium, and the distending atrium results in reducing the patient'sblood pressure from the pretreatment blood pressure, preferably bycausing the atrium to contract at a time when pressure in a ventricle ismaximal so that active force of atrial contraction increases atrialpressure and stretch above maximal passive pressure and stretch causedby contraction of the ventricle.

In another aspect, an embodiment provides a system for reducing bloodpressure. The system may comprise at least one stimulation electrode forstimulating at least one chamber of a heart of a patient with astimulation pattern comprising at least one stimulation pulse. Thesystem may include at least one controller configured to receive inputrelating to the patient's blood pressure and adjust the stimulationpattern based on said blood pressure. For example, the input may includereceiving data sensed by one or more sensors (implanted or external)and/or receiving data provided by a user. For example, duringimplantation and/or periodic checks, a user may provide data regardingmeasured blood pressure. Optionally, the system includes an input portfor receiving this input by wired and/or wireless communication from ameasuring sensor and/or a user interface. The input may comprise datarelating to blood pressure (BP) or a change in BP, which may be measuredas systolic BP (SysBP), diastolic BP, mean arterial BP, and/or any otherrelated BP parameter. For example, at least one sensor may sense thepressure or changes of pressure in one or more cardiac chambers andadjust the stimulation pattern based on the pressure or changes inpressure. In another embodiment, the sensor may sense the pressure inmore than one chamber and adjust the stimulation based on the relationbetween the pressure waveforms of the two chambers.

The controller may be configured to adjust the stimulation pattern byperforming an adjustment process that includes adjusting a parameter ofa first stimulation setting of at least one of the at least onestimulation pulse.

The first stimulation setting may be configured to reduce or preventatrial kick in at least one ventricle.

The parameter may include the adjustment of the AV delay. For example, anatural AV delay may be a range of 120 to 200 ms between the onset ofatrial excitation and the onset of ventricular excitation, whetheroccurring naturally (i.e., without the delivery of a stimulus to theheart) or by setting the timing of the delivery of stimuli to one ormore of the atrium and ventricle. Optionally, adjusting the AV delaymeans adjusting it from a normal AV delay (of, for example, 120 ms) to ashorter AV delay (for example, 0 to 70 ms from the onset of atrialexcitation to onset of ventricular excitation; or an AV delay of 0 to−50 ms in which the ventricular excitation occurs before atrialexcitation). In an embodiment, a stimulation setting having an AV delayof between −50 ms to 70 ms, preferably −40 ms to 60 ms, more preferably−50 ms to 0 or 0 to 70 ms, preferably >0 to 70 ms, is chosen to reduceor prevent atrial kick.

The stimulation pattern that is configured to reduce atrial kick may beconfigured to cause a reduction in blood pressure by at least apredetermined amount within about 3 sec from an application ofelectricity to the heart, and to maintain a reduction in blood pressurefor a time interval of at least 1 minute. For example, a stimulationpattern may be selected and/or adjusted based on feedback relating toone or more sensed BP parameters.

The time interval may be at least 5 minutes.

The predetermined amount of blood pressure reduction may be 8 mmHg ormore.

The predetermined amount of blood pressure reduction may be at least 4%of the patient's pretreatment blood pressure.

The patient's blood pressure may not exceed a predetermined averagevalue during the time interval by more than a predetermined degree. Thepredetermined degree may be a difference of about 8 mmHg or less. Insome embodiments, a patient's blood pressure may exceed a predeterminedaverage value for some heartbeats, but the patient's average bloodpressure may not exceed the predetermined average value.

The controller may be configured to execute a plurality of stimulationpatterns and receive for each of the stimulation patterns acorresponding input data relating to the patient's blood pressure duringthe stimulation. The controller may be configured to calculate for eachof the plurality of stimulation patterns at least one blood pressurevariation parameter relating to the input data. The controller may beconfigured to adjust the stimulation pattern according to the bloodpressure variation parameter.

The controller may be configured to adjust the stimulation pattern to bethe one with the best blood pressure variation parameter.

The best blood pressure variation parameter may be one that displays thelowest degree of baroreflex, or the lowest degree or rate of adaptationas detailed herein.

The best blood pressure variation parameter may be one that displays abaroreflex or degree of adaptation within a predetermined range asdetailed herein.

The at least two stimulation patterns of the plurality of stimulationpatterns may each comprise at least one stimulation pulse having astimulation setting configured to reduce or prevent atrial kick in atleast one ventricle and/or to control atrial pressure and/or stretch.The at least two stimulation patterns may differ one from another by thenumber of times or the length of time the at least one stimulation pulseis provided in sequence.

The plurality of stimulation patterns may differ by the number of timesor the length of time that the system is configured to elicit apredetermined AV delay in sequence.

The at least two stimulation patterns of the plurality of stimulationpatterns may differ from another by one or more stimulation settingsincluded within each of the at least two stimulation patterns.

The plurality of stimulation patterns may include a first stimulationpattern and a second stimulation pattern executed after the firststimulation pattern. The second stimulation pattern may have at leastone stimulation setting that was set based on an algorithm using bloodpressure variation parameters relating to the input data of the firststimulation pattern.

The system may comprise a blood pressure sensor for providing the inputdata relating to the patient's blood pressure.

The blood pressure sensor may be implantable.

The blood pressure sensor and the controller may be configured tooperate at least partially as a closed loop.

In another aspect, an embodiment provides a system for reducing bloodpressure. The system may comprise at least one stimulation electrode forstimulating at least one chamber of a heart of a patient with astimulation pulse. The system may comprise a controller. The controllermay be configured to provide a first stimulation pattern comprising atleast one stimulation setting configured to reduce or prevent atrialkick in at least one ventricle for a first time interval and to receivea first input data relating to a patient's blood pressure during saidfirst time interval. The controller may be configured to calculate atleast one blood pressure variation parameter relating to the first inputdata. The controller may be configured to adjust at least one parameterof a second stimulation pattern comprising a second stimulation settingconfigured to reduce or prevent atrial kick in at least one ventricle.The second stimulation setting may be based upon the at least one bloodpressure variation parameter. The controller may be configured toprovide the second stimulation pattern for a second time interval.

In another aspect, an embodiment may provide a system for reducing bloodpressure. The system may comprise at least one stimulation electrode forstimulating at least one chamber of a heart of a patient with astimulation pulse. The system may comprise at least one controllerconfigured to execute a stimulation pattern comprising at least onestimulation setting configured to reduce or prevent atrial kick in atleast one ventricle. The stimulation pattern may be selected to cause animmediate reduction in blood pressure from an initial pressure value toa reduced pressure value and to maintain a patient's average bloodpressure at rest at least 8 mmHg below the initial pressure.

The reduced blood pressure value may be maintained for a time intervalof at least 1 minute.

In another aspect, an embodiment provides a kit for reducing bloodpressure. The kit may comprise at least one device for setting astimulation pattern for reducing blood pressure. The device may compriseat least one stimulation electrode. The device may comprise a controllerfor setting an adjustable stimulation pattern and a set of instructionsfor adjusting the stimulation pattern based on input relating to patientblood pressure.

In another aspect, an embodiment provides a system for reducing bloodpressure. The system may comprise at least one stimulation electrode forstimulating at least one chamber of a heart of a patient. The system maycomprise at least one controller configured to execute a stimulationpattern comprising at least one stimulation pulse having at least onestimulation setting configured to reduce or prevent atrial kick in atleast one ventricle. The at least one stimulation setting may beconfigured such that maximum atrial stretch is at a value that is aboutequal to or lower than the maximum atrial stretch of the same heart whennot receiving stimulation.

In any of the embodiments described herein, atrial stretch may bemeasured, calculated, and/or estimated as known in the art. Atriumcontraction is known to affect atrial pressure and atrial stretch. Thepressure and the stretch of an atrium depend on atrial volume, whichdepends on the amount of blood inside the atrium and the active forcegenerated by the contraction of the muscle. In a healthy heart, as theatrium contracts, atrial pressure builds up. Atrial pressure drops whenatrial contraction stops and blood is flowing out of the atrium to fillthe ventricle. Then, when the ventricles contract, the AV valve closesand the atrium starts to fill again, since there is no valve thatprevents the flow of blood from the venous system to the atrium.Pressure generated in the ventricle also increases atrial pressure viavarious mechanisms, one of which relates to the bulging of the AV valveinto the atria. An increase in atrial pressure that occurs against aclosed AV valve will also increase atrial stretch that relates to atrialvolume and atrial pressure. The contraction of the atrium when the AVvalve is closed increases both atrial pressure and atrial stretch sincethe closed valve prevents reduction in volume. An increase in stretch inthe atrium stimulates baroreceptors (also known as stretch receptors)present in the atrium wall. These baroreceptors are involved in hormonaland/or neuronal reduction of blood pressure. Accordingly, in someembodiments, atrial stretch determination may include measuring atrialpressure. In some embodiments, atrial stretch determination may includemeasuring or estimating the dimension of an atrium (e.g., diameter,size, or circumference). In some cases, when a single atrial contractionoccurs per cardiac cycle, the amount of blood in the atrium is expectedto be larger than when the atrium contracts twice during a singlecardiac cycle. Thus, if atrial contraction is performed once per cardiaccycle, and atrial contraction is fully against a closed valve, atrialpressure and/or atrial stretch may be higher than in cases when theatrium contracts twice per cycle. However, when the atrium contractsonly against a closed valve there is also no atrial kick, and in someembodiments a balance may be struck (per cardiac cycle and/or per pacingpattern) between values set for atrial pressure (and atrial stretch) andatrial kick.

The at least one stimulation setting may be configured to cause anatrium to be at maximum contraction when the AV valve is open.

The at least one stimulation setting may be configured to alter themechanics of at least one atrial contraction such that the mechanics ofthe at least one atrial contraction are different from the mechanics ofa previous natural atrial contraction. The mechanics of atrialcontraction may be assessed using any known technique including, forexample, ultrasound (e.g., echocardiography or cardiac echo).

The at least one stimulation setting may be configured to reduce theforce of at least one atrial contraction. The force of atrialcontraction may be reduced, for example, by temporarily generatingatrial spasm or atrial flutter. One example is the delivery of a burstof rapid stimulation pulses to the atrium for a short period ofpredefined time. The force of atrial contraction can be calculated fromsensing of atrial pressure and/or a derivative thereof such as wallmotion or flow using any known means. Such sensing may be used as afeedback in a closed loop and/or occasionally (e.g., upon implantationand/or checkups).

The at least one stimulation setting may be configured to prevent atleast one atrial contraction. Atrial contraction may be prevented, forexample, by temporarily generating atrial spasm or atrial flutter. Oneexample is the delivery of a burst of rapid stimulation pulses to theatrium for a short period of predefined time.

In another aspect, an embodiment provides a system for reducing bloodpressure. The system may comprise at least one stimulation electrode forstimulating at least one chamber of a heart of a patient. The at leastone controller may be configured to execute a stimulation pattern ofstimulation pulses to the heart of a patient. The at least onecontroller may be configured to receive input relating to the patient'sAV valve status. This input may be provided by wired or wirelesscommunication from an implanted or external acoustic sensor or bloodflow sensor and/or via a user interface. The at least one controller maybe configured to adjust the at least one stimulation pattern based onsaid valve status.

The input relating to the patient's AV valve status may be indicative ofthe timing of closure of the AV valve.

The input relating to the patient's AV valve status may be providedbased on a heart sound sensor.

The input relating to the patient's AV valve status may be providedbased on a blood flow sensor.

The blood flow sensor may include an implanted sensor.

The blood flow sensor may include an ultrasound sensor for sensing bloodflow through the AV valve.

The blood flow sensor and the controller may be configured to operate atleast partially as a closed loop.

The stimulation pattern may comprise at least one stimulation pulseconfigured to reduce or prevent the atrial kick in at least oneventricle.

The step of adjusting the at least one stimulation pattern may includeadjusting the AV delay of at least one stimulation pulse.

In another aspect, an embodiment provides a system for reducingventricular filling volume in a patient having a pretreatmentventricular filling volume. The system may comprise a stimulationcircuit configured to deliver a stimulation pulse to at least onecardiac chamber. The system may comprise at least one controllerconfigured to execute the delivery of one or more stimulation patternsof stimulation pulses to at least one cardiac chamber. At least one ofthe stimulation pulses may have a first stimulation setting and at leastone of the stimulation pulses may have a second stimulation settingdifferent from the first stimulation setting. At least one of the firststimulation setting and the second stimulation setting may be configuredto reduce or prevent atrial kick, thereby reducing the ventricularfilling volume from the pretreatment ventricular filling volume.

The first stimulation setting and the second stimulation setting may beconfigured to reduce or prevent atrial kick.

The first stimulation setting may have a different AV delay than the AVdelay of the second stimulation setting.

At least one of the one or more stimulation patterns may be repeated atleast twice in a period of one hour.

The at least one controller may be configured to execute the one or morestimulation patterns consecutively for a time interval lasting 10minutes or longer. The first stimulation setting may be configured toreduce or prevent atrial kick in at least one ventricle for at least 50%of the time interval.

The second stimulation setting may have a longer AV delay than the firststimulation setting.

The second stimulation setting has a longer AV delay than the firststimulation setting.

The one or more consecutive stimulation patterns may comprise at leastone stimulation pulse having the first stimulation setting for at leastabout 85% of the time interval.

The time interval may be at least 30 minutes long.

The time interval may be at least one hour long.

The time interval may be at least 24 hours long.

The one or more consecutive stimulation patterns may comprise at leastone stimulation pulse having a third stimulation setting different fromthe first stimulation setting and the second stimulation setting andconfigured to reduce or prevent atrial kick in at least one ventricle.

The one or more consecutive stimulation patterns may comprise at leastone stimulation pulse having a third stimulation setting different fromthe first stimulation setting and the second stimulation setting andconfigured not to reduce or prevent atrial kick in at least oneventricle for less than about 50% of the time interval.

The one or more consecutive stimulation patterns may comprise a thirdstimulation configured not to reduce or prevent atrial kick in at leastone ventricle for about 20% or less of the time interval.

The one or more stimulation patterns may comprise a sequence of 10-60stimulation pulses having the first stimulation setting. The firststimulation setting may be configured to reduce or prevent atrial kickin at least one ventricle, and a sequence of 1-10 heartbeats embeddedwithin the 10-60 stimulation pulses. The sequence of 1-10 heartbeats mayhave a longer AV delay than the first stimulation setting.

The sequence of 1-10 heartbeats may include at least one stimulationpulse having a first stimulation setting configured to reduce or preventatrial kick in at least one ventricle.

The sequence of 1-10 heartbeats may include at least one stimulationpulse having a second stimulation setting.

The sequence of 1-10 heartbeats may include a natural AV delay.

At least one heartbeat of the sequence of 1-10 heartbeats may occurwithout stimulation.

The first stimulation setting may be configured to reduce atrial kick inat least one ventricle and the second stimulation setting may beconfigured to reduce the baroreflex response or adaptation to thereduction in atrial kick such that the increase in blood pressure valuesoccurring between stimulation pulses is limited to a predeterminedvalue.

The second stimulation setting may be configured to allow an increase inblood pressure for about 1 heartbeat to 5 heartbeats.

The stimulation pattern may include multiple stimulation pulses havingthe first stimulation setting.

The stimulation pattern may include multiple stimulation pulses havingthe second stimulation setting.

Between about 1% of the multiple stimulation pulses and 40% of themultiple stimulation pulses of the stimulation pattern may have thesecond stimulation setting.

The stimulation pattern may include a ratio of stimulation pulses havingthe first stimulation setting to the stimulation pulses having thesecond stimulation setting that corresponds to a ratio of time constantsof a response to increase and decrease in blood pressure.

The first stimulation setting may include a first AV delay and thesecond stimulation setting may include a second AV delay. The first AVdelay may be shorter than the second AV delay.

The stimulation pattern may include multiple stimulation pulses havingthe first stimulation setting.

The stimulation pattern may include multiple stimulation pulses havingthe second stimulation setting.

Between about 1% of the multiple stimulation pulses and 40% of themultiple stimulation pulses of the stimulation pattern may have thesecond stimulation setting.

The stimulation pattern may include a ratio of stimulation pulses havingthe first stimulation setting to the stimulation pulses having thesecond stimulation setting that corresponds to a ratio of time constantsof the response to increase and decrease in blood pressure.

The stimulation pattern may include a ratio of about 8 to about 13stimulation pulses having the first stimulation setting to about 2 toabout 5 the stimulation pulses having the second stimulation setting.

One of the first stimulation setting and the second stimulation settingmay be configured to invoke a hormonal response from the patient's body.

In another aspect, an embodiment provides a system for reducingventricular filling volume of a patient having a pretreatmentventricular filling volume. The system may comprise a stimulationcircuit configured to deliver a stimulation pulse to at least onecardiac chamber. The system may comprise at least one controllerconfigured to execute the delivery of one or more stimulation patternsof stimulation pulses to at least one cardiac chamber. At least one ofthe stimulation pulses may include a setting configured to cause aventricular excitation to commence between about 0 ms and about 70 msafter the onset of atrial excitation, thereby reducing the ventricularfilling volume from the pretreatment ventricular filling volume. Forexample, the processor circuit may be configured to operate in anoperating mode in which one or more excitatory pulses are delivered tothe ventricle between about 0 ms and about 70 ms after the onset ofatrial excitation in at least one atrium occurs, or between about 0 msand about 70 ms after one or more excitatory pulses are delivered to theatrium.

In some embodiments, the timing of a sensed atrial excitation may bedetermined by taking into account a delay between actual onset ofexcitation and the sensing thereof. For example, if a sensing delay isestimated to be 20-40 ms, and stimulation pulses are to be delivered0-70 ms after onset of atrial excitation, a system may be set to deliverpulses between 40 ms before the next anticipated sensing event to 30 msafter the next anticipated sensing event or 30 ms after the next sensingevent. Likewise, if the stimulation pulses are to be delivered to theventricle 0-50 ms before onset of atrial excitation, assuming the same20-40 ms sensing delay, a system may be set to deliver pulses between 40ms before the next anticipated sensing event to 90 ms before the nextanticipated sensing event. Sensing delays may be due to one or more of adistance between the site of onset of excitation and a sensingelectrode, the level of the electrical signal, characteristics of thesensing circuit, and the threshold set of a sensing event. The delay mayinclude, for example, the duration of the signal propagation from theorigin of excitation to the electrode location, the duration related tothe frequency response of the sensing circuit, and/or the durationnecessary for the signal propagation energy to reach a level detectableby a sensing circuit. The delay may be significant and can range, forexample, between about 5 ms to about 100 ms. One approach for estimatingthe delay is to use the time difference between an AV delay measuredwhen both atrium and ventricle are sensed and the AV delay when theatrium is paced and the ventricle is sensed. Other approaches may usecalculation of the amplifier response time based on the set threshold,signal strength, and frequency content. Other approaches may includemodifying the delay used with atrial sensing until the effect on bloodpressure is the same as the effect obtained by pacing both atrium andventricle with the desired AV delay.

In another aspect, a system is provided for reducing ventricular fillingvolume in a patient having a pretreatment ventricular filling volume.The system may include a stimulation circuit configured to deliver astimulation pulse to at least one cardiac chamber. At least onecontroller may be configured to execute the delivery of one or morestimulation patterns of stimulation pulses to at least one cardiacchamber for a time interval lasting 10 minutes or longer. At least oneof the stimulation pulses may have a first stimulation settingconfigured to reduce or prevent atrial kick in at least one ventriclefor at least 5 minutes of the time interval and at least one of thestimulation pulses has a second stimulation setting different from thefirst stimulation setting, thereby reducing the ventricular fillingvolume from the pretreatment ventricular filling volume.

In another aspect, a method is provided for reducing ventricular fillingin a patient having a pretreatment ventricular filling volume. Themethod may include a step of delivering one or more stimulation patternsof stimulation pulses to at least one cardiac chamber for a timeinterval lasting 10 minutes or longer. At least one of the stimulationpulses may have a first stimulation setting configured to reduce orprevent atrial kick in at least one ventricle for at least 5 minutes ofthe time interval and at least one of the stimulation pulses has asecond stimulation setting different from the first stimulation setting.

Other systems, methods, features, and advantages of the invention willbe, or will become, apparent to one of ordinary skill in the art uponexamination of the following figures and detailed description. It isintended that all such additional systems, methods, features andadvantages be included within this description and this summary, bewithin the scope of the invention, and be protected by the followingclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention can be better understood with reference to the followingdrawings and description. The components in the figures are notnecessarily to scale, emphasis instead being placed upon illustratingthe principles of the invention. Moreover, in the figures, likereference numerals designate corresponding parts throughout thedifferent views.

FIG. 1 shows the systolic blood pressure of a hypertensive patientreceiving a stimulation signal, plotted against time;

FIG. 2 shows an enlarged view of the portion of FIG. 1 marked by dashedrectangle A;

FIG. 3A depicts an enlarged view of the portion of FIG. 2 between timepoint a and point a′;

FIG. 3B depicts an enlarged view of the portion of FIG. 1 marked bydashed rectangle A′;

FIG. 4 depicts an enlarged view of the portion of FIG. 1 marked bydashed rectangle B;

FIG. 5A depicts an enlarged view of the portion of FIG. 1 marked bydashed rectangle C;

FIG. 5B depicts an enlarged view of the portion of FIG. 5A between timepoint c and point c′;

FIG. 6 shows the systolic blood pressure of a hypertensive patientreceiving a stimulation signal, plotted against time;

FIG. 7 shows the systolic blood pressure of a hypertensive patientreceiving a stimulation signal, plotted against time;

FIG. 8 is a flow chart showing an exemplary method for setting and/orselecting a stimulation pattern;

FIG. 9 is a schematic diagram illustrating an exemplary system forreducing blood pressure;

FIG. 10A shows a time plot including: electrocardiogram, aortic pressureand left ventricular pressure of a healthy canine heart;

FIG. 10B shows a time plot including: electrocardiogram, aortic pressureand left ventricular pressure of a healthy canine heart;

FIG. 11A shows a time plot of a hypertensive canine heart, includingright atria pressure, magnified diastolic portion of right ventricularpressure, right ventricular pressure and electrocardiogram;

FIG. 11B shows a time plot of a hypertensive canine heart, includingright atria pressure, magnified diastolic portion of right ventricularpressure, right ventricular pressure and electrocardiogram;

FIG. 12 shows a right atria pressure, magnified diastolic portion ofright ventricular pressure, right ventricular pressure, left ventricularpressure and at the same graph aortic pressure and an electrocardiogramof a hypertensive canine heart;

FIG. 13 is a flow chart showing an exemplary method for reducing bloodpressure;

FIG. 14 is a flow chart showing an exemplary device for reducing bloodpressure, which may perform one or more of the methods described herein,such as the methods of FIG. 13 and FIG. 23;

FIG. 15 is a schematic diagram illustrating an artificial valveaccording to an embodiment;

FIG. 16 shows the systolic blood pressure of a hypertensive patientreceiving a stimulation signal, plotted against time;

FIG. 17 is a graph showing ventricular volume, ventricular pressure,atrial pressure, and electrocardiogram (ECG) plotted against time,highlighting the isovolumic phase and rapid ejection phase of a singlecardiac cycle;

FIG. 18 is a set of graphs illustrating an electrocardiogram (ECG),right ventricle pressure (RV Press), right atrial pressure (RA Press),aortic pressure (Ao Press), and left ventricle pressure (LV Press)traced over a period of time in which stimulation is changed from sinusrhythm to pacing of an atria and a ventricle at an AV delay of 2 ms,showing a significant increase in atrial pressure, according to anembodiment;

FIG. 19 is a set of graphs illustrating an electrocardiogram (ECG),right ventricle pressure (RV Press), right atrial pressure (RA Press),aortic pressure (Ao Press), and left ventricle pressure (LV Press)traced over a period of time in which stimulation is changed from sinusrhythm to pacing of an atria and a ventricle at an AV delay of 40 ms,showing no significant increase in atrial pressure;

FIGS. 20A-20C are graphs of atrial pressure over time, illustratingdifferent degrees of overlapping between an atrial pressure resultingfrom an atrial contraction and passive pressure build-up in the atriumtaking place at different time intervals between them, with FIG. 20Aillustrating an example of no overlap between atrial pressure resultingfrom an atrial contraction and passive pressure build-up in the atrium,with FIG. 20B illustrating an example for combining an atrial pressureresulting from an atrial contraction and passive pressure build-up inthe atrium at a delay of 30 ms between their onsets, and with FIG. 20Ccomparatively illustrating different degrees of overlap due to delays of0, 10, 20, 30, 40, 50 and 60 ms;

FIG. 21 is a graph plotting a patient's average blood pressure during a24-hour period;

FIG. 22 is a graph plotting a patient's average blood pressure during a24-hour period, when not treated and when treated according to anembodiment; and

FIG. 23 is a flow chart showing an exemplary method for controllingatrial pressure and atrial stretch, according to an embodiment.

DETAILED DESCRIPTION

The human heart comprises two atria and two ventricles. In a normalheart cycle, cardiac contraction begins with atrial contraction, whichis followed by contraction of the ventricles.

The mechanical process of cardiac contraction is controlled byconduction of electricity in the heart. During each heartbeat, a wave ofdepolarization is triggered by cells in the sinoatrial node. Thedepolarization propagates in the atria to the atrioventricular (AV) nodeand then to the ventricles. In a healthy heart, atrioventricular delay(AV delay), i.e., the delay time between the onset of atrial excitationand the onset of ventricular excitation, is normally between 120milliseconds (ms) and 200 ms. The relative timing of the atrialcontraction and the ventricular contraction is affected inter alia bythe relative timing of excitation of each chamber and by the time neededby the chamber to generate mechanical contraction as a result of theelectrical activation (depending on size, speed of propagation,differences in myocyte properties, etc.).

Before contraction, the heart muscle is relaxed and blood flows freelyinto the ventricles from the atria, through a valve between them. Thisperiod can be divided into a rapid filling phase and a slow fillingphase. The rapid filling phase commences just after the relaxation ofthe ventricle, during which blood from the venous system and the atriarapidly fills the ventricle. The rapid filling phase lasts forapproximately 110 ms and is followed by the slow filling phase, whichlasts until the start of the contraction of the atria. The duration ofthe slow filling phase depends on the heart rate. Thereafter, as anatrium contracts, pressure increases in the atrium and causes blood toflow more rapidly into the ventricle. This contribution of atrialcontraction to ventricle filling is known as the “atrial kick.” Atrialkick is normally responsible for about 10%-30% of ventricle filling.

FIG. 17 illustrates changes in ventricular volume, ventricular pressure,atrial pressure, and cardiac electrical activity over time through asingle cardiac cycle. As used herein, a cardiac cycle is a period oftime between two relaxations of the ventricle, between which only asingle contraction of the ventricle takes place. The duration of thecardiac cycle is inversely proportional to the heart rate, such that thecardiac cycle duration increases as the heart rate decreases anddecreases as the heart rate increases. At a typical human rate of 75beats per minute, one cardiac cycle lasts about 0.8 seconds.

Referring to FIG. 17, a cardiac cycle may be said to begin at the onsetof atrial excitation, when a P wave is observed in the ECG. Then, about50-70 ms thereafter the atrium begins to contract, for a period of about70-110 ms. As the atrium contracts, pressure builds up inside the atriumand reaches a maximal value after which the atrium begins to relax andpressure reduces. The maximal value is represented at the point 1701 inFIG. 17. Meanwhile, the electrical stimulus propagates to the ventricleand the onset of ventricle excitation occurs at an AV delay of about120-200 ms later (the AV delay can be about 250 ms or even more in someunhealthy individuals). This excitation of the ventricle manifests onthe ECG as the QRS complex. As the ventricle contracts, pressure buildsup within it and passively closes the valves between each of the atriaand a respective ventricle (AV valves), thus stopping the flow of bloodfrom the atrium into the ventricle and preventing backflow.

During the next period of the ventricular contraction, a period known asisovolumic contraction, or isovolumic phase, that lasts approximately 50ms, all ventricle valves are closed and the pressure in the ventriclerapidly rises with no significant change in volume, as shown in FIG. 17by the ventricular pressure line and the ventricular volume line withinthe vertical lines 1703 and 1704 demarcating the isovolumic phase.

As ventricular pressure further increases, at the time indicated by line1704 in FIG. 17, the valve between the ventricle and artery opens andblood is ejected out of the ventricle and away from the heart. Thisphase of ventricular contraction is divided into a rapid ejection phaseand a decreased ejection phase. The rapid ejection phase lastsapproximately 90-110 ms, during which about ⅔ of the stroke volume isejected. The rapid ejection phase is represented in FIG. 17 as theperiod between lines 1704 and 1705.

During the isovolumic phase and in the beginning of the rapid ejectionphase, the contraction of the ventricle typically causes a passiveincrease in atrial pressure. This increase in atrial pressure isconsidered to be attributable to a mechanical effect of the ventricles'contraction on the associated atria. For example, this atrial pressureincrease may be due to the atria being tightly associated with the muchlarger ventricle; as the large ventricle muscle contracts, it affectsthe attached atrium. The increased atrial pressure may also result fromthe backward bulging of valves into the atria, which may be due to theincreasing pressure in the ventricles. Passive filling of the atriumcontinues throughout the cardiac cycle (including between points 1701and 1702) since there is no valve between the atrium and the vascularsystem. This continual passive filling in conjunction with the increasedpressure due to the mechanical effects of the ventricular contraction,may contribute to the increase in atrial pressure. Thus, the passiveatrial pressure increase peaks at some time between the second half ofthe isovolumic phase (i.e., about 25-35 ms after commencement of theisovolumic phase) and the beginning of the rapid ejection phase (e.g.,within the first approximately 10 ms of the rapid ejection phase), asrepresented in FIG. 17 by point 1702. The passive atrial pressurebuild-up may be higher than the maximal atrial pressure due to atrialcontraction, as shown in FIG. 17 by the higher atrial pressure at point1702 relative to the lower atrial pressure at point 1701.

The rapid ejection phase is followed by the decreased ejection phaselasting about 130-140 ms. Thereafter, all valves close again and theventricle relaxes in isovolumic relaxation for about 60-80 ms, duringwhich the pressure in the ventricle drops. At this time, the valvesbetween the ventricle and the atria reopen allowing blood to flow freelyinto the ventricle, after which a new cardiac cycle may commence.

Controlling Atrial Pressure and Atrial Stretch

In the present disclosure, cardiac stimulation may be used to increaseatrial pressure and stretch and thereby reduce blood pressure (BP).Cardiac stimulation may achieve increased atrial pressure by stimulatingthe heart such that an atrial pressure resulting from atrial contractionof an atrium overlaps in time a passive pressure build-up of the atrium,such that an atrial pressure of the atrium resulting from thestimulation is a combination of the atrial pressure resulting fromatrial contraction and the passive pressure build-up and is higher thanan atrial pressure of the atrium would be without the stimulation.Embodiments may reach maximum atrial pressure by causing maximum atrialcontraction at a period of time overlapping the maximum passive increasein atrial pressure. For example, cardiac stimulation may be used toreach maximum atrial pressure resulting from atrial contraction during atime between about 25-35 ms after the beginning of the isovolumic phaseand about 10 ms after the end of the isovolumic phase. Increasing atrialpressure (by overlapping in time atrial pressure resulting from atrialcontraction with passive increase in atrial pressure) increases atrialstretch, which is known to affect blood pressure through hormonal and/orneuronal pathways. For example, an increase in atrial stretch may causesecretion of atrial natriuretic hormone or atrial natriuretic peptide,which in turn may reduce blood pressure.

In some embodiments, maximum atrial pressure resulting from atrialcontraction is considered to have occurred at a period of timeoverlapping the maximum passive increase in atrial pressure if maximumatrial pressure resulting from atrial contraction fully or at leastpartially coincides with the maximum passive increase in atrialpressure. For example, maximum atrial pressure resulting from atrialcontraction is considered to have occurred at a period of timeoverlapping the maximum passive increase in atrial pressure if themaximum atrial contraction is expected to occur within about 20 msbefore or after the expected maximum passive increase in atrialpressure. In some embodiments, maximum atrial pressure means the highestpart of the contraction or passive pressure increase, having a pressurevalue that is at least approximately 25% above the pressure value of theatrium at rest. Optionally, maximum atrial pressure resulting fromatrial contraction is considered to have occurred at a period of timeoverlapping the maximum passive increase in atrial pressure if only onepeak in pressure is observed from the atrial contraction and passivepressure increase, or if two peaks are observed, the maximum atrialpressure resulting from atrial contraction and the maximum passiveincrease in atrial pressure are no more than about 30 ms apart.Optionally the overlap in time can be detected mathematically byanalyzing measured values and/or visually, for example, by plottingatrial pressure over time or atrial pressure change over time.

BP or a change in BP may be measured as systolic BP (SysBP), diastolicBP, mean arterial BP, BP in one or more chambers, and/or any otherrelated BP parameter. In some embodiments, an electrical stimulator,such as a pacemaker or other type of device having a pulse generator,may be used to stimulate a patient's heart to reduce blood pressure.Electrodes electrically connected to the electrical stimulator with awired or wireless connection may be placed adjacent a cardiac chamber.The electrical stimulator may be operated to deliver a pulse to thecardiac chamber via the electrode.

In some embodiments, stimulating the heart such that the atrium reachesan increased (and preferably, maximum) atrial pressure resulting fromatrial contraction at a period of time overlapping the (preferably,maximum) passive pressure increase in atrial pressure may consequentlyreduce blood pressure. For simplicity, in the following description,such stimulation may be termed “AC (Atrial Contraction) stimulation.” ACstimulation may include delivering at least one stimulation pulse to atleast one chamber of a heart such that the atrium reaches maximum atrialpressure resulting from atrial contraction during the period between thesecond half of the isovolumic phase and the first approximately 10 ms ofthe rapid ejection phase. Such a stimulation pulse will be referred toherein as an “AC stimulation pulse” or “AC pulse.”

As used herein, a “stimulation pulse” may comprise a sequence of one ormore excitatory electrical pulses (or stimulation pulses) delivered toone or more chambers of the heart within the timeframe of a singleheartbeat (when a single heartbeat is defined as a period of timebetween two relaxations of the ventricle, between which only a singlecontraction of the ventricle takes place). Optionally, such excitatoryelectrical pulses (or stimulation pulses) are also termed pacing pulses.For example, in some embodiments, a stimulation pulse may comprise oneor more electrical pulses delivered to one or more locations in aventricle and/or one or more electrical pulses delivered to one or morelocations in an atrium. Thus, in some embodiments, the stimulation pulsemay include a first electrical pulse delivered to an atrium and a secondelectrical pulse delivered to the corresponding ventricle. In someembodiments, the stimulation pulse may include a first electrical pulsedelivered to an atrium, a second electrical pulse delivered to thecorresponding ventricle, and a third electrical pulse delivered to theatrium after it has exited a refractory period associated with the firstpulse. In some embodiments, a stimulation pulse may include a singlepulse being delivered to a plurality of locations on one or morechambers of the heart.

In some embodiments, an AC pulse may be delivered at such timingrelative to the cardiac cycle so as to have an atrial pressure resultingfrom atrial contraction of an atrium overlap in time a passive pressurebuild-up of the atrium, such that an atrial pressure of the atriumresulting from the stimulation is a combination of the atrial pressureresulting from atrial contraction and the passive pressure build-up andis higher than an atrial pressure of the atrium would be without thestimulation. Preferably, an AC pulse may be delivered at such timingrelative to the cardiac cycle so as to have the atrium reach maximumatrial pressure resulting from atrial contraction at a time overlappingthe maximum passive pressure increase of the atrium. Optionally, thistiming of delivery of the AC pulse is set according to one or moresensed events, such as events relating to a cardiac cycle.

For example, atrial and/or ventricular excitation may be sensed and theAC pulse may be delivered to the atrium and/or ventricle accordingly.For example, a pacing pulse may be delivered to the atrium at suchtiming as is expected to be within about −20 to 30 ms from the sensingor pacing of a ventricle and at least approximately 20 milliseconds fromthe end of the refractory period of the atrium. Optionally, the heartrate and a ventricle excitation or contraction may be sensed and thetiming of a next ventricle contraction or excitation may be estimated,and the AC pulse may be delivered so that an atrial pressure resultingfrom an atrial contraction in a future heartbeat overlaps in time apassive pressure increase of the atrium. Optionally, the AC pulse may bedelivered so that an atrial contraction in a future heartbeat reachesmaximum atrial pressure resulting from atrial contraction at a timeoverlapping the maximum passive pressure increase of the atrium. Forexample, the AC pulse may comprise a stimulus that is delivered to theatrium about 30 to 0 ms before the expected ventricular excitation orabout 50-120 ms before the start of the expected ventricularcontraction.

In some embodiments, the stimulation pulse may include a first atrialexcitation that is sensed or paced, an electrical pulse that isdelivered to the corresponding ventricle, and another electrical pulsethat is delivered to the atrium after the atrium has exited a refractoryperiod associated with the first excitation. For example, the timeperiod between the first atrial excitation (e.g., delivery of a firstexcitatory pulse to the atrium) and the delivery of another excitatorypulse to the atrium may be between about 150 to 250 ms.

In some embodiments, an AC pulse comprises a first electrical pulsedelivered to an atrium and a second electrical pulse delivered to thecorresponding ventricle. The relative timing of the first electricalpulse and second electrical pulse is controlled to cause the atrium tocontract at a time within the period between the second half of theisovolumic phase and early in the rapid ejection phase of the heart atthat heartbeat. Since the time between delivery of an excitatory pulseand the onset of contraction is longer for a ventricle than for anatrium, the delay between the delivery of the first pulse and the secondpulse may have a negative value, for example, between about −20 and 0ms.

This precise timing may vary between different patients and betweendifferent conditions (e.g., different placement of one or moreelectrodes on the chambers). Accordingly, in some embodiments thesettings of an AC pulse may be adjusted, for example, upon implantationof a device and/or periodically, for example, upon a periodic check orduring use (for example, based on feedback from one or more associatedsensors).

For example, AC pulses having different settings may be delivered to thepatient and atrial pressure may be sensed, until a desired atrialpressure resulting from atrial contraction of an atrium overlapping intime a passive pressure build-up of the atrium is sensed. In someembodiments, a desired atrial pressure may be any pressure that exceedsan atrial pressure that the atrium would reach without the stimulation.Optionally, the desired atrial pressure may be selected as the highest(or being one of the highest) among a plurality of atrial pressuresresulting from a plurality of AC pulses having different settings. Forexample, the AC pulses might differ by having different AV delay betweena sensed or paced atrial contraction and a paced or sensed ventricularcontraction. As a result, one or more AV pulse settings may be selectedfor use during a period of time for a given patient.

For example, AC pulses having different settings may be delivered to thepatient and atrial pressure may be sensed, until a desired degree ofoverlap is observed between the maxima of maximum atrial pressureresulting from atrial contraction and passive pressure build-up of theatrium. For example, the AC pulses might differ by having different AVdelay between a sensed or paced atrial contraction and a paced or sensedventricular contraction. As a result, one or more AV pulse settings maybe selected for use during a period of time for the given patient.

Optionally, the AC pulses may be delivered as part of pacing patternsthat differ in the settings of different pulses within the patterns, andone or more patterns may be selected for repeated use, based on one ormore parameters relating to the choice of pulses configured to reduce orprevent atrial kick as well as on the aforementioned pressure overlap.

A stimulation setting means one or more parameters of one or morestimulation pulses delivered in a single cardiac cycle. For example,these parameters may include, one or more of: power, a time intervalbetween electrical pulses that are included in a single stimulationpulse (e.g., AV delay or delay between two atrial pulses), a period ofdelivery with respect to the natural rhythm of the heart, the length ofa stimulation pulse or a portion thereof, and the site of deliverybetween two or more chambers and/or within a single chamber. An ACstimulation setting, or “AC setting,” may include a setting of one ormore AC pulses.

In some embodiments, sensing may include sensing electrical activity ofone or more chambers of the heart, such as one or more of atrialexcitation and/or ventricle excitation. In some embodiments, sensingincludes using the sounds of a cardiac cycle to detect cardiac activity.For example, closure of the AV valves results in the first sound of aheartbeat. This closure also signifies the beginning of the isovolumicphase. Optionally, based on the timing of closure of the AV valve andthe heart rate, a pulse setting may be selected for a future AC pulse.For example, a stimulatory pulse may be provided to the atrium about80-10 milliseconds before the next anticipated closure of the AV valve.

Optionally, a refractory period of a cardiac chamber (e.g., an atrium)may be estimated as known in the art. The AC pulse may comprisedelivering to the atrium a stimulation pulse that elicits atrialcontraction. For example, the stimulation pulse may be timed fordelivery after the end of the refractory period, or if delivered duringthe relative refractory period, have such electrical properties so as toelicit a contraction despite the relatively early timing.

In some embodiments, a heart rate is sensed as known in the art, forexample, based on electric activity, sound, pressure, and/or any othermeans.

In some embodiments, one or more AC pulses may be provided as part of asequence of pulses, or a pacing pattern, encompassing a plurality ofheartbeats. A pacing pattern may comprise a plurality of pacing pulseshaving different settings. Optionally, all of the pulses may be ACpulses but some may have different pulse settings than others.Optionally, only some of the pulses in a given pattern may be configuredto cause the atrium to reach an increased, or maximum, atrial pressureresulting from atrial contraction during the period between the secondhalf of the isovolumic phase and early in the rapid ejection phase.

It is further noted that one or more pulse settings (e.g., timingbetween events, sensed and/or delivered) may be optimized and/oradjusted to suit a specific patient and/or variation in the patient'scardiac functioning.

For example, a patient's heart rate may vary for many reasons, includingactivity and time of day. Changes in heart rate may cause changes in therelative timing of cardiac events. Accordingly, one or more of thefollowing parameters may be sensed and used to optimize and/or adjustthe pulse setting.

For example, aortic pressure and/or sound associated with the opening ofone or both cardiac valves can be used to pin point the timing of thebeginning and/or end of the isovolumic phase and/or the beginning of therapid ejection phase. Such timing may be compared with the time that apulse is delivered and/or a cardiac event is sensed such that thedesired timing of contraction would be achieved more precisely and/ormore repeatedly.

In another example, one may measure the timing from the delivery orsensing of an excitation stimulus (to an atrium and/or to a ventricle)to when peak pressure is sensed in the atrium (due to contraction orpassive pressure build-up).

Another option may be to adjust the AC pulse settings according to oneor more of heart rate, patient activity, posture, and/or respirationrate.

In fact, a combination of the above may be used for adjustment and/oroptimization. For example, one may measure one or more of the timingbetween atrial excitation and maximum atrial pressure resulting fromatrial contraction, ventricle excitation, maximal atrial passivepressure, and the timing of the isovolumic phase and/or rapid ejectionphase. Optionally, one may measure atrial pressure resulting from thedelivery of stimulation pulses and adjustment may include selecting astimulation setting according to the measured resulting pressure. Thesemeasurements may also be correlated with the patient's heart rate atdifferent conditions. Using the specific measurements taken from thepatient, the pulse setting may be adjusted or optimized.

The optimization and/or adjustment as discussed above may be performedas a closed loop, for example, in some cases where a sensor isassociated with the implanting stimulation device. Alternatively, theoptimization and/or adjustment may be performed as an open loop. Theoptimization and/or adjustment may be an ongoing process (especially ifthe sensor is implanted, for example, according to heart rate) and/ormay be performed during implantation when a patient is provided with adevice, occasionally, and/or upon need. Finally, the optimization and/oradjustment may be automated and/or involve a medical practitioner.

Embodiments may implement different pacing techniques to achieve ACstimulation and a desired overlap of the atrial pressure resulting fromatrial contraction and the passive increase in atrial pressure. In someembodiments, AC stimulation may include pacing the atrium at an atrialrate substantially equal to an intrinsic ventricular rate or pacing theatrium at an atrial rate that is greater than the intrinsic ventricularrate. In addition, different pacing techniques may be implemented toachieve the desired AC stimulation with either a single contraction ofthe atrium or a double contraction of the atrium.

For a single contraction of the atrium, pacing techniques that achievethe desired AC stimulation may, for example, include:

-   -   a. Sensing the atrium (optionally involving anticipating the        atrium activation) and pacing the ventricle;    -   b. Sensing the ventricle and pacing the atrium, which may        require that the pacing of the atrium be performed before the        anticipated time of ventricle sensing; or    -   c. Pacing the atrium and pacing the ventricle.

For a double contraction of the atrium, pacing techniques that achievethe desired AC stimulation may, for example, include:

-   -   a. Sensing first the atrium activation, sensing the ventricle,        and pacing the atrium in the same cardiac cycle to create a        second contraction;    -   b. Sensing the atrium, pacing the ventricle, and pacing the        atrium in the same cardiac cycle to create a second contraction;    -   c. Pacing the atrium, sensing the ventricle, and pacing the        atrium again; or    -   d. Pacing the atrium, pacing the ventricle, and pacing the        atrium again.

Other pacing techniques may be employed to achieve the desired ACstimulation and overlap of the atrial pressure resulting from atrialcontraction and the passive increase in atrial pressure. Accordingly,notwithstanding the particular benefits associated with the pacingtechniques described herein, the present embodiments should beconsidered broadly applicable to any pacing technique that provides thedesired AC stimulation and overlap.

FIGS. 18-19 are graphs illustrating two different stimulation patternsdelivered to a healthy anesthetized canine heart, showing anelectrocardiogram (ECG), right ventricle pressure (RV Press), rightatrial pressure (RA Press), aortic pressure (Ao Press), and leftventricle pressure (LV Press) traced over a period of time. According toone embodiment, FIG. 18 illustrates a change of stimulation from sinusrhythm to pacing of the atria and ventricle at an AV delay of 2 ms,which resulted in an overlap of the pressure due to atrial contractionand the atrial pressure due to passive pressure increase. In thisexample, the pacing at an AV delay of 2 ms caused an overlap in time ofthe maximal pressure due to atrial contraction and the maximal atrialpressure due to passive pressure increase, as well as a measurableincrease in atrial pressure, and therefore also atrial stretch. Forcomparative purposes, FIG. 19 illustrates an AV delay of 40 ms, whichshowed a lesser degree of overlap and yielded no significant increase inatrial pressure. Optionally, a higher degree of overlap may be definedas a function of the proximity of atrial pressure maxima—the closer themaxima, the higher the overlap, until the maxima overlap completely anda single maximum pressure is observed. Optionally, the degree of overlapis a function of the maximal sensed atrial pressure, with a higherpressure maximum value characterizing a higher degree of overlap.

In the experiments associated with FIGS. 18-19, a healthy canine heartwas equipped with a pacemaker configured with algorithms that allowpacing at a specified AV delay. The pacemaker was connected to the heartvia two pacing electrodes, one in the right atrial appendage and one inthe right ventricular apex. Four solid state pressure sensors wereinserted into the right atria, the right ventricle, the left ventricle,and the aorta. A single lead ECG was also connected to the animal. Thesensors were connected to amplifiers and a data acquisition system (DAQsystem), and the signal was sampled at the rate of 1 kHz and plotted, toprovide the graphs shown in FIGS. 18-19. As shown, the graphs includefrom bottom to top the following plots: ECG, RV pressure, RA pressure,Ao pressure, and LV pressure.

In each experiment, the heart was allowed to contract using the naturalsinus rhythm for a few beats and was then paced at both the atria andthe ventricle with the designated AV delay.

Referring to each of FIGS. 18-19, during the period of time of sinusrhythm 1802, two distinct increases in atrial pressure can be seen. Thefirst atrial pressure increase 1804 follows the atrial electricalactivity (the P wave 1806) and corresponds to the contraction of theatria. The second atrial pressure increase 1808 occurs during theisovolumic contraction of the ventricle (characterized by a rapidincrease in ventricle pressure) and continues through a short initialperiod of the rapid ejection phase (starting when the aortic pressurestarts to increase). The effect of ventricle contraction on the atrialpressure causes the second atrial pressure increase 1808. As shown inthe RA Press plots of FIGS. 18-19, the maximum atrial pressure reachedduring the isovolumic contraction is slightly higher than the maximumatrial pressure reached during contraction of the atria.

As described above, embodiments may include provisions to maximizeatrial pressure, and therefore maximize atrial stretch. In particular,stimulation may be delivered to an atrium at such timing relative to thecardiac cycle so as to cause the atrium to reach maximum atrial pressureresulting from atrial contraction at a time overlapping the maximumpassive pressure increase of the atrium. FIG. 18 illustrates one exampleof this timing, in which the atria and ventricle are paced at an AVdelay of 2 ms, as represented by the atrial pace 1810 followed 2 mslater by the ventricular pace 1812. FIG. 18 shows three instances ofthis pacing.

Referring to the portions of the right atrial pressure plot (RA Press)in FIG. 18, with the three instances of pacing, significant increases inatrial pressure can be seen at points 1814, 1816, and 1818. Thosesignificant pressure increases result from the simultaneous, or nearlysimultaneous, atrial pressure increases due to atrial contraction and tocontraction of the ventricle. In other words, comparing the sinus rhythmportion 1802 of the right atrial pressure plot to the AV delay pacedportion 1803 of the right atrial pressure plot, the first and secondatrial pressure increases 1804 and 1808 of the sinus rhythm portion 1802are essentially superimposed in the AV delay paced portion 1803 suchthat the atrial pressure increases 1804 and 1808 are combined to providethe higher atrial pressure increases 1814, 1816, and 1818.

Optionally, an AC pulse may have a setting that includes a predefined AVdelay between a sensed or paced atrial excitation and a paced or sensedventricular excitation. The AV delay may be selected such that theatrial pressure resulting from atrial contraction and passive atrialpressure build-up overlap, essentially as described above, and such thatthe atrial pressure of the atrium that is a combination of the atrialpressure resulting from atrial contraction and the passive pressurebuild-up, is higher than an atrial pressure of the atrium would bewithout the stimulation (or with a different stimulation). The AV delaymay be selected such that the maxima of atrial pressure resulting fromatrial contraction and passive atrial pressure build-up overlap,essentially as described above. This setting may vary between patientsand may, in time, even change for a given patient. Nonetheless, in mostcases it is expected that an AV delay between about 30 ms and about 0 mswill be effective. In some patients (such as the examples shown withhealthy canine hearts shown in FIG. 18), the AV delay between atrialexcitation and ventricular excitation may be between about 30 ms andabout 0 ms or between about 20 ms and about 0 ms.

It is noted that when sensing is used to detect a cardiac event uponwhich the AV delay is set, the following is optionally taken intoaccount: firstly, when electrical excitation is sensed, there is a delaybetween actual excitation and its detection. This may be due to thelocation of the sensing electrode as well as to limitations of thesensing system. Thus, for example, the time period between a sensedatrial excitation and delivery of a pacing pulse to a ventricle would beshorter than the desired AV delay. When sensing is based on a mechanicalevent (e.g., contraction or valve closure), the time between actualexcitation and the occurrence of the mechanical event also needs to betaken into account. Some examples for the relative timing of sensedevents and the delivery of pacing pulses are disclosed herein. Inaddition, as detailed in this application, the settings may be adjustedto suit the specific times of a patient upon implantation and/orperiodically.

In contrast to the surprising beneficial results achieved by pacing withan AV delay that causes atrial contraction of an atrium to overlap intime a passive pressure build-up of the atrium, thereby providing anatrial pressure of the atrium that is a combination of the atrialpressure resulting from atrial contraction and the passive pressurebuild-up and is higher than an atrial pressure of the atrium would bewithout the stimulation (as in the example of FIG. 18), FIG. 19illustrates an AV delay that is short relative to normal AV delays(e.g., 140 ms in canine hearts), but does not provide a significantincrease in atrial pressure. As shown in FIG. 19, after the sinus rhythmportion 1802, the heart was paced at an AV delay of 40 ms during the AVdelay paced portion 1803, as represented by the atrial pace 1910followed 40 ms later by the ventricular pace 1912. FIG. 19 shows twoinstances of this pacing. Referring to the portions of the trace of theatrial pressure (RA Press) shortly after the pacing, despite the short40 ms AV delay relative to a normal 140 ms AV delay, the 40 ms AV delaydid not result in a significant increase in atrial pressure over theatrial pressure increases 1804 and 1808 of the sinus rhythm portion1802. Instead, as shown in FIG. 19, the 40 ms AV delay resulted in twoseparate atrial pressure increases 1904 and 1908, which were roughlyequivalent to the previous atrial pressure increases 1804 and 1808.

Comparing FIG. 18 with FIG. 19 therefore shows that significantlyincreased atrial pressure occurs when the contraction of the atria andthe second half of the isovolumic contraction or early part of the rapidejection phase of the ventricle occur simultaneously, or nearlysimultaneously, as in FIG. 18. That significant increase in atrialpressure may provide a desired release of stress-related hormones forreducing blood pressure. Accordingly, embodiments pace the atria andventricle at an AV delay of about 2 ms.

FIGS. 20A-20C depict some theoretical examples for combining atrialpressure due to atrial contraction and passive pressure build-up in theatrium. In these examples, different degrees of overlap are shown, asdetailed below, and pressure due to atrial contraction and passivepressure build-up is summed. Initially, atrial pressure was tracedduring a natural cardiac cycle, such as shown in FIGS. 18 and 19 in theperiod of time of sinus rhythm 1802. From this tracing, atrial pressuredue to atrial contraction 1804 and passive pressure build-up 1804 wereextracted. In FIG. 20A, the two pressure curves (corresponding to 1802and 1804 of FIG. 18) were summed assuming a 60 ms delay between theonset of atrial contraction and the onset of passive pressure build-up.As seen, atrial contraction lasted about 60 ms and reached a maximumpressure of nearly 1.5 mmHg, while passive pressure build-up lastedabout 50 ms and reached a maximum pressure a little higher than 2 mmHg.Since the atrial contraction lasted about 60 ms (which is roughly thesame as the assumed delay), the two pressure increases are observed asdistinct portions in the trace, having two distinct maxima, and themaximal pressure observed is that of passive pressure build-up 1804.

FIG. 20B illustrates in more detail a theoretical combining of atrialpressure due to atrial contraction and passive pressure build-up in theatrium. In this tracing, the onset of passive pressure build-up 1804(dashed line) was assumed to take place 30 ms after the onset of atrialcontraction 1802 (dotted line), as shown. The two traces were summed andthe sum was traced as pressure tracing 204 (solid line). As seen in thisexample, due to some degree of overlap, the combined pressure line 204had a maximum pressure that was slightly higher than the maximumpressure observed in passive pressure build-up 1804 (dashed line)without the overlap, while two maxima are still seen, one correspondingto each of the combined tracings 1802 and 1804.

Although timing a maximum atrial pressure due to atrial contraction tooccur simultaneously with a maximum passive pressure build-up—such thatthe maxima occur as a singular event—may yield a maximum attainableatrial pressure, embodiments may provide significant beneficialincreases in atrial pressure through a range of times beyond thatsingular event. In other words, to stimulate a heart to obtain an atrialpressure that is a combination of the atrial pressure resulting fromatrial contraction and the passive pressure build-up and is higher thanan atrial pressure of the atrium would be without stimulation, thetiming of stimulation need only provide that the combination (e.g., sum)of the atrial pressure resulting from atrial contraction and the passivepressure build-up is greater than the maximum pressure generated in theatrium without stimulation. If the maximum atrial pressure due to atrialcontraction occurs simultaneously with the maximal passive pressurebuild-up of the atria, the combination (e.g., sum) of those pressures islikely to be greater than each of the individual pressures. However,providing a combined atrial pressure that is greater than both of theindividual pressures is not limited to that singular event ofsimultaneously occurring maxima points and will be true for a range oftimes over which the pressures overlap each other, as discussed in moredetail below.

In FIG. 20C, pressure due to atrial contraction and passive pressurebuild-up were combined at various hypothetical degrees of overlapbetween them, thus exemplifying how controlling the relative timing ofatrial and ventricular contraction may affect the combined atrialpressure. In this example, like in FIG. 20B, a time delay between theonset of atrial contraction and onset of passive pressure buildup wasassumed, and accordingly, at each point in time the atrial pressure dueto atrial contraction was summed with the passive pressure build-up atthe same point in time, thereby providing a combined pressure. Thecombined (e.g., summed) pressures of different examples are traced inFIG. 20C.

Trace 201 of FIG. 20C is identical to the trace shown in FIG. 20A, witha delay of 60 ms between the onset of pressure due to atrial contractionand passive pressure build-up. In trace 207, on the other hand, theatrial pressure due to atrial contraction and the passive pressurebuild-up were combined at close to maximal overlap (a 0 ms delay betweenthe onset of the two changes in pressure, which due to the differentdurations may not exactly coincide), i.e., assuming that they bothcommenced at about the same time. As seen, in this case, trace 207 showsthe sum of the pressures reaching a single maximum value of about 3.5mmHg. Similarly, at a delay of 10 ms (trace 206) a single maximum wasobserved, slightly later than in trace 207 and having a lower maximumvalue than that of trace 207. As the time delay increased, in trace 205(20 ms delay), the tracings begin to separate but still yield a singlemaximal value (between 2.5 mmHg and 3 mmHg). Trace 204 (30 ms delay;which is identical to the trace shown in FIG. 20B) clearly displays twomaxima, but there is still sufficient overlap and the sum of atrialpressure is slightly higher than that of trace 201. Finally, at evenlower degrees of overlap, in traces 203 and 202 (40 ms and 50 ms delays,respectively), while there is some overlap between pressure due toatrial contraction and passive pressure build-up, in each of the tracesthe two maxima are more than 30 ms apart and the maximal pressure isabout the same as in trace 201, where no overlap was shown.

In some embodiments, a stimulation pattern may be used to lower theblood pressure by applying stimulation patterns comprising one or moreAC pulses or consisting of AC pulses, only intermittently. For example,applying intermittent AC pulses may allow natural heartbeats to occur inbetween the AC pulses and/or the pulses that are not configured to causean overlap between the atrial pressure due to atrial contraction andatrial pressure due to passive pressure build-up (or do not cause anoverlap of the respective maxima), thereby providing an atrial pressureof the atrium that is a combination of the atrial pressure resultingfrom atrial contraction and the passive pressure build-up and is higherthan an atrial pressure of the atrium would be without the stimulation.Optionally, the periods of time between the application of AC pulses maybe selected according to time constants of secretion and/or absorptionof natriuretic peptides, such that sufficient stimulation will bedelivered to essentially provide the desired effect but without muchexcessive stimulation. This may have the benefit of reducing the powerused by an implanted device and/or reduce the degree of manipulation ofthe heart.

An exemplary method 230 for controlling atrial pressure is depictedschematically in FIG. 23. Method 230 may be performed by an implanteddevice as described herein. Accordingly, the device may be configured toperform any or all steps of method 230. Similarly, method 230 mayinclude any steps that the device is configured to perform. For example,method 230 may include any of the functions discussed below with respectto device 50 of FIG. 14.

In some embodiments, method 230 may include sensing cardiac event(s), asshown in step 231. This event, or events, may include one or moreelectrical events and/or mechanical events and may be sensed as known inthe art and as described in further detail herein. For example, thesensed events may include sensing of atrial and/or ventricularexcitation and/or the timing of steps in the cardiac mechanical activitysuch as opening and/or closure of one or more cardiac valves. The sensedevents may include a deduction of relative timing between cardiacevents. In some embodiments, step 231 may include triggering one or morecardiac events, such as atrial or ventricular excitation. Optionally,step 231 may include sensing an intrinsic heart rate, or setting theheart rate. For example, step 231 may include sensing the closure of theAV valve thus defining the beginning of the isovolumic phase, and/orsensing the opening of the aortic valve thus defining the point in timeat which the rapid ejection phase begins. Step 231 may also includedetermining the time difference between sensing the activation of theventricle or stimulation of the ventricle and the closure of the AVvalve that define the beginning of the isovolumic phase.

Method 230 may include a step 232 in which pulse settings are selected.The settings may include or comprise setting a time interval betweenatrial and ventricular excitations. The settings may include selecting aratio between atrial excitations and ventricular excitations for a givenstimulation pulse. The settings may include power settings based on thesensed or estimated timing of delivery of an excitatory pulse in arelative refractory period of the target chamber.

Method 230 may include a step 233 of delivering at least one stimulationpulse using the pulse settings optionally set in step 232, which pulsesettings may be selected based on the timing of the sensed events instep 231. In some embodiments, an excitatory current may be applied toboth ventricles, at the same time or in sequence. In some embodiments inwhich both ventricles are paced in sequence, a time interval may bemeasured between the onset of excitation of at least one atrium (e.g.,the right atrium) and the onset of excitation of the correspondingventricle to be paced (e.g., the right ventricle). In some embodimentsin which a time interval is set to be zero or negative, step 233 may beperformed before or at the same time as step 231. In some embodiments,the time interval may be measured in milliseconds.

The pulse settings selected in step 232 may be selected based onfeedback. In such cases, method 230 may include sensing atrial pressure,as shown in step 234. For example, feedback information may be obtainedby using an implanted sensor for feedback and adjustment of pulsesettings, on an ongoing basis and/or on a periodic basis, such as duringimplantation and/or periodic checkups. Method 230 may include a step 235of estimating the overlap in time between an atrial pressure(preferably, a maximum atrial pressure) resulting from atrialcontraction and a passive pressure build-up of the atrium (preferably, amaximum passive pressure build-up). For example, the estimating of step235 may include detecting a number of maxima in atrial pressure andtheir length in time and/or the distance in time between the maxima,and/or detecting a number of maxima and minima in atrial pressure andestimating the duration of a contraction or change in pressure based onthe time between maxima and minima, and/or detecting the maximal valueof atrial pressure compared to atrial pressure of the same heart withoutthe stimulation. This comparison may be performed using a stored valuecorresponding to a pressure measured before treatment commenced, and/ormay include a step of sensing atrial pressure in at least one heartbeatwithout the delivery of a stimulation pulse, according to method 230.

Method 230 may include step 236 of adjusting the pulse setting selectedin step 232 based on the sensed overlap estimated in step 235. Forexample, step 236 may include adjusting the time interval to provide thehighest degree of overlap observed between a plurality of settings.Optionally, a higher degree of overlap may be defined as a function ofthe proximity of atrial pressure maxima—the closer the maxima, thehigher the overlap, until the maxima overlap completely and a singlemaximum pressure is observed. Optionally, the degree of overlap is afunction of the maximal sensed atrial pressure, with a higher pressurecharacterizing a higher degree of overlap.

As shown by the arrow directed from step 236 to step 231 in FIG. 23,step 231, step 232, step 233, step 234, and/or step 235 may be repeatedafter performing step 236. In some embodiments, the time pulse settingmay be initially set at a first value during step 231 and, based onfeedback sensing performed during steps 234 and 235, the pulse settingmay be adjusted (e.g., a time interval reduced or increased) during step236 until the degree of overlap is within a given range (or above orbelow a given value).

The steps of method 230 may be performed in any order. For example, thesteps may be performed in the order indicated by the arrows shown inFIG. 23. In another embodiment, step 232 may be performed before step231.

The timing of atrial contraction, atrial excitation, ventricularcontraction, closing and/or opening of the AV valve(s), and/or the flowor lack thereof of blood from one or more atria to the respectiveventricle(s) and/or blood pressure may be detected by any method knownin the art and may be used as feedback control. In some embodiments, theonset of excitation may be used as a trigger for the delivery of anexcitatory stimulus to one or more heart chambers (e.g., one or twoventricles or an atrium and a ventricle). The sensed information may beadditionally or alternatively used in the adjusting of a timing intervalof the device.

Embodiments may provide a method for adjusting a pulse setting in asystem for controlling blood pressure. The method may include receivingatrial pressure data associated with an atrium of a heart of a patientduring at least one cardiac cycle. The atrial pressure data may resultfrom the system's delivering to the heart a stimulation pulse having afirst pulse setting. The method may further comprise analyzing theatrial pressure data, and providing an adjusted second pulse settingaccording to the analysis, with the adjusted second pulse setting beingdifferent from the first pulse setting. The analyzing may includeanalyzing the atrial pressure data to estimate an overlap in timebetween an atrial pressure resulting from atrial contraction and apassive pressure build-up of the atrium. The analyzing may also includeplotting the atrial pressure data and/or mathematically analyzing theatrial pressure data.

Embodiments may provide a system for reducing blood pressure, which mayinclude components such as those shown in FIG. 14. A system may includemeans for providing information about pressure variation in an atriumduring at least one cardiac cycle of a heart, means for generatingstimulation pulses, and means for applying the stimulation pulses to atleast one cardiac chamber. The means for generating stimulation pulsesmay be arranged to generate the stimulation pulses so as to control thetiming of an atrial contraction relative to the timing of a ventricularcontraction in a single cardiac cycle according to the information aboutpressure variation in the atrium. In one implementation, a means forproviding information may first sense the information (e.g., pressuresand the time between changes in pressure) and a means for generatingstimulation pulses may later time stimulation based on the information.

The information about pressure variation in an atrium may includeinformation about occurrence of an atrial contraction and/or informationabout occurrence of a ventricular contraction. The information mayinclude information about the relative timing between a maximum atrialpressure resulting from atrial contraction and a maximum passivepressure build-up of the atrium. The information may include informationrelating to the occurrence and/or timing of one or more cardiac eventsas described in this specification, including for example one or more ofcontraction of an atrium, contraction of a ventricle, opening of anatrioventricular valve, closure of an atrioventricular valve, electricalactivity of the atria, electrical activity of the ventricle, blood flow,a refractory period of an atrium, and heart rate.

The means for generating stimulation pulses may be arranged forgenerating for at least one cardiac cycle: at least one atrialstimulation pulse for generating an atrial contraction; and/or at leastone ventricular stimulation pulse for generating a ventricularcontraction. The means for generating stimulating pulses may bearranged: for generating the at least one atrial stimulation pulse, onthe basis of the information about the occurrence of the atrialcontraction and/or the information about the occurrence of theventricular contraction, in a timed relationship to the occurrence ofthe atrial contraction and/or to the occurrence of the ventricularcontraction; and/or for generating the at least one ventricularstimulation pulse on the basis of the information about the occurrenceof the ventricular contraction and/or the information about theoccurrence of the atrial contraction, in a timed relationship to theoccurrence of the ventricular contraction and/or to the occurrence ofthe atrial contraction. The information about the occurrence of theatrial contraction may include information about the occurrence of a Pwave pattern in the natural stimulation pattern of a cardiac cycle. Theinformation about the occurrence of the ventricular contraction mayinclude information about the occurrence of a QRS complex in the naturalstimulation pattern of a cardiac cycle.

The timing of atrial contraction relative to ventricular contraction maycorrespond to an AV delay within a range of about 30 ms to about 0 ms.The means for generating stimulation pulses may be arranged to generatethe stimulation pulses so as to: provide an excitatory stimulus to theatrium within a range of about 30 ms to about 0 ms before ventricularexcitation occurs; provide an excitatory stimulus to the ventriclewithin a range of about 30 ms to about 0 ms after atrial excitationoccurs; and/or provide an excitatory stimulus to the atrium and thenwithin a range of about 30 ms to about 0 ms later provide an excitatorystimulus to the ventricle.

Other embodiments may provide another system for reducing bloodpressure, which may also include components such as those shown in FIG.14. In those other embodiments, a system for reducing blood pressure mayinclude means for providing information about timing of one or moreheart activity events, means for generating stimulation pulses, andmeans for applying the stimulation pulses to at least one cardiacchamber. The information about timing of one or more heart activityevents may include at least one of: occurrence of an atrial contractionof an atrium, occurrence of a ventricular contraction of a ventricle,opening of an atrioventricular valve, closure of an atrioventricularvalve, electrical activity of the atria, electrical activity of theventricle, blood flow, atrial pressure of the atrium, changes in atrialpressure of the atrium, a refractory period of an atrium, and heartrate. The means for generating stimulation pulses may be arranged togenerate the stimulation pulses so as to set a timing of atrialcontraction relative to ventricular contraction based on theinformation.

The timing of atrial contraction relative to ventricular contraction maycorrespond to an AV delay within a range of about 30 ms to about 0 ms.The means for generating stimulation pulses may be arranged to generatethe stimulation pulses so as to: provide an excitatory stimulus to theatrium within a range of about 30 ms to about 0 ms before ventricularexcitation occurs; provide an excitatory stimulus to the ventriclewithin a range of about 30 ms to about 0 ms after atrial excitationoccurs; and/or provide an excitatory stimulus to the atrium and thenwithin a range of about 30 ms to about 0 ms later provide an excitatorystimulus to the ventricle.

The information about timing of one or more heart activity events mayinclude information about timing between two or more heart activityevents in a single cardiac cycle.

The means for generating stimulation pulses may be arranged forgenerating for at least one cardiac cycle: at least one atrialstimulation pulse for generating an atrial contraction; and/or at leastone ventricular stimulation pulse for generating a ventricularcontraction. The means for generating stimulating pulses may bearranged: for generating the at least one atrial stimulation pulse, onthe basis of the information about the occurrence of the atrialcontraction and/or the information about the occurrence of theventricular contraction, in a timed relationship to the occurrence ofthe atrial contraction and/or to the occurrence of the ventricularcontraction; and/or for generating the at least one ventricularstimulation pulse on the basis of the information about the occurrenceof the ventricular contraction and/or the information about theoccurrence of the atrial contraction, in a timed relationship to theoccurrence of the ventricular contraction and/or to the occurrence ofthe atrial contraction. The information about the occurrence of theatrial contraction may include information about the occurrence of a Pwave pattern in the natural stimulation pattern of a cardiac cycle. Theinformation about the occurrence of the ventricular contraction mayinclude information about the occurrence of a QRS complex in the naturalstimulation pattern of a cardiac cycle.

Controlling Atrial Kick

In some embodiments, stimulating the heart such that the contribution ofatrial contraction to the filling of the ventricles (atrial kick) isreduced or even prevented, reduces cardiac filling at the end ofdiastole and consequently reduces blood pressure. For simplicity, in thefollowing description, such stimulation will be termed “BPR (BloodPressure Reducing) stimulation.” BPR stimulation may include deliveringat least one stimulation pulse to at least a chamber of a heart suchthat atrial kick is reduced or even prevented. Such a pulse will bereferred to herein as a “BPR stimulation pulse” or “BPR pulse” herein.As described above, a “stimulation pulse” may comprise a sequence of oneor more electrical pulses delivered to one or more chambers of the heartwithin the timeframe of a single heartbeat or cardiac cycle. Forexample, in some embodiments, a stimulation pulse may comprise one ormore electrical pulses delivered to one or more locations in a ventricleand/or one or more electrical pulses delivered to one or more locationsin an atrium. Thus, in some embodiments, the stimulation pulse mayinclude a first electrical pulse delivered to an atrium and a secondelectrical pulse delivered to the corresponding ventricle. In someembodiments a stimulation pulse may include a single pulse beingdelivered to a plurality of locations on one or more chambers of theheart.

A stimulation setting means one or more parameters of one or morestimulation pulses delivered in a single cardiac cycle. For example,these parameters may include one or more of: power, a time intervalbetween electrical pulses that are included in a single stimulationpulse (e.g., AV delay), a period of delivery with respect to the naturalrhythm of the heart, the length of a stimulation pulse or a portionthereof, and the site of delivery between two or more chambers and/orwithin a single chamber. A BPR stimulation setting, or “BPR setting,”may include a setting of one or more BPR pulses.

A stimulation pattern may include a series of pulses having identicalstimulation settings or a stimulation pattern may include multiplepulses each having different stimulation settings. For example, astimulation pattern may have one or more pulses having a first settingand one or more pulses having a second setting that is different fromthe first setting. When stating that a stimulation pattern has asetting, it is understood that this means a stimulation pattern mayinclude at least one stimulation pulse having that setting. It is alsounderstood that, in some embodiments a stimulation pattern may includeone or more cardiac cycles where no stimulation pulse is delivered, inwhich case the pulse(s) may be viewed as being delivered at zero power.A stimulation pattern may include a plurality of identical pulses or asequence of pulses including two or more different settings. Twostimulation sequences in a pattern may differ in the order of pulsesprovided within a setting. Two or more stimulation sequences mayoptionally differ in their lengths (in time and/or number ofheartbeats). In some embodiments, a stimulation pattern may includepulses having BPR settings. In some embodiments, a stimulation patternmay include pulses that do not have BPR settings.

Examples of stimulation settings that are configured to reduce orprevent atrial kick in at least one ventricle may include any of thestimulation settings disclosed herein that are configured to cause areduction of a patient's ventricular filling volume from thepretreatment ventricular filling volume. This may be caused by having atleast part of an atrial contraction take place against a closed AVvalve. Some such examples include:

-   -   a. Delivering one or more stimulation pulses to a ventricle of a        patient 0-50 ms before the onset of excitation in an atrium of        the patient. Optionally, this delay is set based on sensing of        atrial excitation. Optionally, this includes delivering one or        more stimulation pulses to the atrium 0-50 ms after the delivery        of stimulation pulses to the ventricle. Optionally, this is        performed at a rate that is slightly higher than the natural        heart rate of the patient.    -   b. Delivering one or more stimulation pulses to a ventricle of a        patient 0-70 ms after the onset of excitation in an atrium of        the patient. Optionally, this delay is set based on sensing of        atrial excitation. Optionally, this includes delivering one or        more stimulation pulses to the atrium 0-70 ms before the        delivery of stimulation pulses to the ventricle. Optionally,        this is performed at a rate that is slightly higher than the        natural heart rate of the patient.

Some embodiments may provide a system for reducing blood pressureconfigured to deliver stimulation at a rate higher than the naturalheart rate based on sensed natural heart rate or natural excitation. Forexample, the system may be configured to sense the natural excitationbetween delivery of stimulation pulses and if a natural activity issensed, the system may be configured to inhibit the delivery of thestimulation pulse to the chamber. If in a given time frame the amount ofsensed activations exceeds a threshold, the natural heart rate may beregarded as higher than the rate of delivery of the stimulation pulses,in which case the rate of delivery may be increased, e.g., toaccommodate increased heart rate of a patient. On the other hand, if ina given time frame the amount of sensed activations is lower than athreshold (this threshold may be 0), the natural heartbeat may beregarded as lower than the rate of delivery of the stimulation pulses,in which case the rate of delivery may be reduced, e.g., to avoid overexcitation of a patient's heart. To achieve this effect, according toone embodiment, a system for reducing blood pressure may include asensor for sensing an excitation rate of at least one of an atrium and aventricle of a patient's heart, a stimulation circuit configured todeliver stimulation pulses to an atrium and a ventricle, and a processorcircuit coupled to the stimulation circuit. Optionally, a sensor forsensing the excitation rate of at least one of an atrium and a ventriclemay comprise an electrode for sensing atrial excitation. The processorcircuit may be configured to detect the patient's heart rate based onthe sensing and operate in an operating mode in which a stimulationpulse is provided to each of the at least one of an atrium and aventricle. The stimulation pulse may be delivered at a rate that ishigher than the sensed excitation rate and may be configured tostimulate the ventricle at a time between about 50 ms before and about70 ms after stimulation of the atrium.

Reducing atrial kick may have an immediate effect on blood pressurewhile hormone mediated mechanisms may take a longer period. While somedevices may be configured to have both an immediate and a hormonemediated effect, optionally, some of the BPR settings and/or stimulationpatterns may be configured to reduce or prevent atrial kick without asignificant increase in atrial stretch. For example, when the AV valvecloses at a time that atrial contraction is at peak pressure orthereafter, premature closure of the valve does not increase atrialstretch. Thus, in some embodiments, a device may be configured to causethe relative timing of atrial excitation and ventricular excitation tobe comparable with an AV delay that is at least 40 ms long or at least50 ms long. Atrial stretch may be measured, calculated, and/or estimatedas known in the art. In some embodiments, atrial stretch determinationmay include measuring atrial pressure. In some embodiments, atrialstretch determination may include measuring or estimating the dimensionof an atrium (e.g., diameter, size, or circumference).

In some embodiments, atrial kick may be reduced because the BPRstimulation setting may be set such that atrial contraction of a cardiaccycle is incomplete when the AV valve is open. In some embodiments,atrial contraction may take place completely or in part against a closedAV valve. In some embodiments atrial contraction may be prevented orreduced in pressure and/or force.

In some embodiments, only one or more ventricles may be stimulated andthe stimulation pulse may be timed to have an abnormal AV delay (e.g.,50 ms before to 120 ms after atrial excitation). In some embodiments, aBPR stimulation setting may include the delivery of at least oneelectrical pulse or stimulus to one or more atria. In some embodiments,this at least one atrial stimulus may cause atrial contraction. In someembodiments, the at least one atrial stimulus may interfere with atrialcontraction. In some embodiments, the at least one atrial pulse maycause an atrial spasm or another type of inefficient atrial contraction.

The reduction in blood pressure resulting from BPR stimulation may beobserved practically immediately upon application of the stimulationsignal (e.g., within 1 or 3 seconds (sec) or within 1, 3, or 5heartbeats) and may reach a minimal blood pressure value within lessthan 5 heartbeats from the beginning of stimulation.

By controlling the settings of BPR stimulation, one may control thedegree to which BP is reduced. This degree is sometimes patient specificand/or related to the precise positioning of one or more stimulationand/or sensing electrodes in or on the heart.

Adaptation

-   -   a. The inventors found that while stimulation is maintained,        blood pressure may display an adaptation pattern wherein blood        pressure increases after a time (some of which often occurs in a        short time being less than 5 minutes or even less than a        minute), and potentially reaches near pre-stimulation blood        pressure values (possibly due at least to baroreflex) or even        higher. The adaptation, at least in part, may be attributed to        changes in properties of the cardiovascular system, such as        increase in total peripheral resistance. The inventors further        found that termination of stimulation results in a quick return        of blood pressure to pre-stimulation values or even higher        values, and thereafter that the heart becomes responsive to the        blood pressure reducing stimulation signal at a degree similar        to a heart that was not so stimulated. In addition, it was found        that different stimulation patterns that comprise a plurality of        BPR stimulation settings result in different blood pressure        adaptation patterns.    -   b. Stimulation patterns may, for example, comprise at least a        first stimulation setting and a second stimulation setting        different from the first stimulation setting, the first        stimulation setting and the second setting configured to reduce        or prevent atrial kick and/or to control atrial pressure and/or        stretch. The stimulation pattern may even comprise more than two        different stimulation settings. The second setting in some        embodiments has a longer AV-delay than the first setting. The        second setting in some embodiments may not be configured to        reduce atrial kick and/or to control atrial pressure and/or        stretch.

In FIG. 1, the systolic blood pressure of a hypertensive patientreceiving a stimulation signal is plotted against time. The crossesalong the plotted line depict the peak systolic blood pressure for everyheartbeat. During approximately the first 2 plotted minutes, nostimulation signal was delivered. As seen, the patient's initial bloodpressure was on average more than 150 mmHg. The oscillations in bloodpressure (about ±10 mmHg) are attributed to the breathing cycle, asknown in the art.

Then, a first stimulation pattern was applied during time interval a-a′,a second stimulation pattern was applied during time interval b-b′, anda third stimulation pattern was applied during time interval c-c′. Inbetween the stimulation patterns and after the third stimulationpattern, the heart was not stimulated.

Attention is now drawn to FIG. 2, depicting an enlarged portion of FIG.1 marked by dashed rectangle A. During the time marked by the dashedrectangle in FIG. 2, which corresponds with the time interval a-a′ inFIG. 1, a stimulation commenced and was delivered to the patient's rightatrium and right ventricle, such that the atrium received a BPRstimulation signal (pulse) 2 ms before the ventricle. Stimulation endedat the time marked a′ in FIGS. 1 and 2. During the time interval a-a′,the patient's systolic pressure initially reduced to a minimal valuebelow 110 mmHg, and then gradually increased to intermediate values,between the initial blood pressure and the achieved minimum. At pointa′, stimulation stopped and an immediate overshoot in blood pressure wasobserved, to a value above 170 mmHg. Within about a dozen heartbeats,the blood pressure returned to its initial range.

The changes in blood pressure presented in FIGS. 1 and 2 represent, atleast in part, the cardiovascular system's response to changes in bloodpressure, known as the baroreflex. The baroreflex acts to restore bloodpressure to its pre-stimulation level by changing cardiovascularcharacteristics (e.g., peripheral resistance and/or cardiaccontractility). It may be assumed that the reduction in blood pressurethat resulted from the reduction in ventricular filling provoked abaroreflex response directed towards restoration of the pre-stimulationblood pressure. The effect of the baroreflex on the cardiovascularsystem is evident, for example, at point a′ in FIG. 2. At that point,the stimulation that affected ventricular filling was withdrawn andblood pressure immediately exceeded pre-stimulation blood pressure. Thismay be taken to indicate baroreflex changes to the cardiovascular system(e.g., peripheral resistance increased and contractility increased). Atpoint a′, where stimulation stopped and blood pressure peaked, thebaroreflex responded to the increase in blood pressure by again changingone or more characteristics of the cardiovascular system, this time inorder to lower the blood pressure to the level before the change. As canbe clearly seen, the response of the baroreflex feedback to increase anddecrease in blood pressure is asymmetric in that the response to anincrease in blood pressure is much faster than the response to adecrease in blood pressure. Some embodiments may make use of thisasymmetry of the baroreflex to reduce or even prevent adaptation of thereduction in blood pressure due to reduced filling, for example, bycontrolling a stimulation pattern accordingly, as detailed herein.

FIG. 3A depicts an enlarged view of the curve of FIG. 1 between timepoint a and point a′. In FIG. 3A, an exponential function was fitted tothe plotted curve showing an adaptation response, the functiondescribing a relation between time and SysBP, and having the followingformula:

P=Pi+DP(1−e ^(−t/k))

Where P (in mmHg) denotes the systolic blood pressure, Pi (mmHg) is afirst average reduced blood pressure upon commencement of BPRstimulation, DP (mmHg) is a constant representing the amount of increasein pressure after the initial decline to a new steady state level, k(sec) is a response time constant, e is the mathematical constant, beingthe base of the natural logarithm, and t (sec) is time.

In FIG. 3A, the matching function was as follows:

P=115+23(1−e ^(−t/15.5))

Where Pi was found to be 115 mmHg, DP was 23 mmHg, and k was 15.5 sec.

FIG. 3B depicts an enlarged view of the portion of FIG. 1 marked bydashed rectangle A′. In FIG. 3B, an exponential function was fitted tothe plotted curve showing an adaptation response to the termination ofthe delivery of BPR stimulation. As seen, this response, whichmanifested in a reduction of blood pressure, was faster than theresponse to BPR stimulation.

In FIG. 3B, the matching function was as follows:

P=190−35(1⁻ e ^(−t/4.946))

Where Pi was found to be 190 mmHg, DP was −35 mmHg, and k was 4.946 sec.

As mentioned above, the baroreflex response to a reduction in bloodpressure is much slower than the baroreflex response to an increase inblood pressure. This is indicated by the ratio of the aforementionedtime constants k (about 15 sec to about 5 sec) with a much fasterresponse to the increase in blood pressure. This asymmetry in the speedof the baroreflex response may provide means to design a stimulationpattern that generates an average reduction in blood pressure andreduction or even prevention of adaptation. For example, in a preferredembodiment, a stimulation pattern may alternate between two stimulationsettings in a way that the weighted response favors the changes in thecardiovascular system invoked by increase in blood pressure. In thisembodiment, the heart may be stimulated using a stimulation patternhaving two stimulation settings: the first setting designed to reduceventricular filling and thereby reduce blood pressure, and the secondsetting designed to have normal ventricular filling, or at least ahigher ventricular filling, than that of the first setting. Thisstimulation pattern may comprise pulses having the first setting (BPR)delivered for a period of time that is shorter than the time constant ofthe baroreflex response to the decrease in blood pressure. In such case,adaptation may begin to manifest and blood pressure may increase fromthe reduced level, but may not reach its pre-stimulation level. Thestimulation pattern may also comprise pulses having the second setting(e.g., natural AV delay) delivered for a period of time that is longerthan the time constant of the baroreflex response to increase in bloodpressure. In this case, full advantage may be taken of the baroreflexcaused reduction in blood pressure, and blood pressure may even returnto its level before the stimulation pattern switched to this secondsetting. The weighted response of the baroreflex in such a pattern mayreduce or prevent adaptation while the average pressure may be lowerthan a pre-stimulation level. The relation between the time constantsand the period of time allotted to the delivery of pulses havingdifferent settings may determine the level of baroreflex response thattakes effect during the whole stimulation pattern. If, for a givenstimulation setting, the period of delivery is selected to be shorterthan the time constant of response, the baroreflex may not be able tochange the cardiovascular system back to a pre-stimulation level, and ifthe period selected is greater than the time constant, the baroreflexeffect may be more pronounced.

As seen in FIG. 1, at the interval between points b and b′, a secondstimulation pattern was delivered. FIG. 4 depicts an enlarged version ofthis portion of FIG. 1 (marked by dashed rectangle B in FIG. 1). In thesecond stimulation pattern, a sequence of 12 BPR pulses were deliveredto both an atrium and a corresponding ventricle at an AV delay of 2 ms,followed by 3 heartbeats at which only atrial stimulation and noventricular stimulation was artificially delivered. During these last 3heartbeats, ventricular excitation occurred by the natural conductancethrough the AV node that resulted in an AV delay of ˜180 ms. This secondstimulation pattern was repeated for the duration of the shown timeinterval. In FIG. 4, the exponential function matching the curve wasfound to be the following:

P=112+30(1−e ^(−t/25.5))

As seen, Pi and also DP were comparable to the corresponding values ofthe first stimulation pattern (a-a′ in FIG. 3A). However, k of thesecond pattern was nearly twice the time constant of the firststimulation pattern. In this time interval, adaptation occurred at aslower rate than in FIG. 3A, but blood pressure spiked more than it didin FIG. 3A when the pattern switched between the stimulation pulses.This result demonstrates that the use of a stimulation pattern havingalternating stimulation settings reduced adaptation.

A third stimulation pattern was delivered as well, as seen in FIG. 1,between points c and c′. FIG. 5A depicts an enlarged view of the portionof FIG. 1 marked by dashed rectangle C, which includes the portion ofthe curve between point c and point c′. In the third stimulationpattern, a sequence of 12 BPR pulses was delivered at an AV delay of 2ms, followed by 3 BPR pulses, each with a 120 ms AV delay. This wasrepeated for the duration of the shown time interval.

The portion of the curve of FIG. 5A that is marked by a dashed rectangleis plotted in FIG. 5B. In FIG. 5B, an exponential function was fitted tothe plotted curve showing an adaptation response to the delivery of thestimulation pattern of 12 BPR pulses delivered at an AV delay of 2 msfollowed by 3 BPR pulses, each with a 120 ms AV delay.

In FIG. 5B, the matching function was as follows:

P=109.7+22.3(1⁻ e ^(−t/45.4))

Where Pi was found to be 109.7 mmHg, DP was 22.3 mmHg, and k was 45.4sec. As seen, while the initial reduction in blood pressure wascomparable with the one shown in FIG. 3A (Pi=115 or 109.5), theadaptation time constant (k) was much higher (45.4 sec v. 15.5 sec),meaning that a low blood pressure was maintained for a period of timethat is about 3 times greater than in FIG. 3A.

Attention is now drawn to FIG. 6, wherein a hypertensive patient's heartwas stimulated at a stimulation pattern having a sequence of 12 BPRpulses delivered at an AV delay of 2 ms, followed by 3 BPR pulses, eachwith an 80 ms AV delay.

As seen, in this case, the adaptation rate was very low and almostundetectable at the allotted time interval. An exponential formula couldnot be matched, suggesting that the adaption was extremely slow or didnot exist.

In FIG. 7, a hypertensive patient's heart was stimulated with astimulation pattern having a sequence of 12 BPR pulses delivered at anAV delay of 2 ms, followed by 3 BPR pulses, each with a 40 ms AV delay.Stimulation commenced at point t₁ and ended at point t₂. There was nomeasured adaptation response and the fitting curve was in fact linearand had a fixed average reduced blood pressure of about 112 mmHg, whichis about 31 mmHg lower than the blood pressure immediately before andafter the time interval t₁-t₂.

As apparent from the different stimulation patterns shown before, astimulation pattern comprising at least one BPR stimulation can be setto at least approach one or more targets. For example, in someembodiments, a stimulation pattern may be set to cause an initialreduction in blood pressure (systolic and/or diastolic) that will exceeda predetermined threshold or will be within a predetermined range. In amore specific embodiment, the blood pressure may be reduced by at leasta given percentage or by at least a given measure (e.g., 10 or 20 mmHgor even 30 mmHg) or the blood pressure may be reduced to be within agiven range (e.g., between 90 and 130 mmHg SysBP) or below a giventarget (e.g., 130 mmHg SysBP or less). In some embodiments, a target mayinclude maintaining a reduced blood pressure for a prolonged period oftime within a reduced average range. For example, the pretreatment bloodpressure may be reduced to a predetermined average blood pressure for aperiod of time or a number of heartbeats. In another embodiment, thetarget may include causing a given percentage of heartbeats to be at thereduced range/threshold. In some embodiments, the target may includereducing blood pressure while also reducing the level of spikes betweenstimulation pulses. For example, a stimulation pattern may be used tolower the blood pressure to a constant blood pressure for apredetermined interval of time. In some embodiments, a stimulationpattern may be used to lower the blood pressure without significantlyinfluencing the cardiac output. For example, applying intermittent BPRpulses may allow pulses with a higher (or even full) atrial kick tooccur between BPR pulses. The pulses with a higher (or even full) atrialkick may prevent the BPR pulses from significantly lowering the cardiacoutput. In another embodiment, reducing adaptation that relates tolowering total peripheral resistance together with reduction of bloodpressure (afterload) can positively affect cardiac output by affectingflow via the blood system. In yet another embodiment, pacing at a higherrate than the patient's natural rhythm may avoid a negative effect oncardiac output that might be associated with lower stroke volume.

In some embodiments, a time constant of the change in blood pressure ofa given pattern may be calculated and the stimulation pattern may be setto have one or more BPR stimulation parameters for an amount of time ornumber of heartbeats that are set as a certain percentage of thecalculated time constant. For example, in FIGS. 3A and 3B, k wasmeasured to be about 15 sec for the rate of increase in blood pressureduring delivery of a BPR pulses and about 4.9 sec for the rate ofadaptation to the termination of the delivery of BPR pulses. In someembodiments, it may be desired to prevent blood pressure from increasingbeyond a given value, in which case, the period of delivery of the BPRpulses may be selected to be significantly smaller than k (e.g., 30% to60% of k). In this embodiment, the interval may be selected to be lessthan 15 sec. Such an interval may include about 6-10 sec or about 8-14heartbeats where the heart rate is about 80 heartbeats per minute.

Optionally, it is desired to take advantage of the adaptation responseto the withdrawal of BPR pulses. In such case, a greater portion of kmight be applied. For example, based on FIG. 3B, a period of 3-5heartbeats may be selected (where k is about 4.9 sec). Thus, forexample, based on FIGS. 3A and 3B, the inventors applied the stimulationpattern of FIG. 4.

The stimulation pattern may be set, for example, to be the best of aplurality of stimulation patterns (i.e., the one closest to a set targetparameter) and/or it may be selected as the first tested stimulationpattern that conformed to a set target.

Embodiments of Methods for Setting and/or Selecting a StimulationPattern

An exemplary method 600 for setting and/or selecting a stimulationpattern is schematically depicted in FIG. 8. Method 600 may be performedduring implantation of a device for performing BPR and/or AC stimulationand/or periodically to adjust the device operation parameters and/orcontinuously during operation. Method 600 may be performed by system700, described below. Accordingly, system 700 may be configured toperform any step of method 600. Similarly, method 600 may include anysteps system 700 is configured to perform. For example, method 600 mayinclude any of the functions discussed below with respect to system 700.Additionally, method 600 may be performed by device 50, described belowin reference to FIG. 14. Method 600 may include any steps device 50 isconfigured to perform.

Throughout the present disclosure, the terms “first,” “second,” and“third” are not meant to always imply an order of events. In some cases,these terms are used to distinguish individual events from one anotherwithout regard for order.

In some embodiments, step 601 may include setting a target bloodpressure value. This target may be an absolute blood pressure value(e.g., a target blood pressure range, a target threshold of spike value,and/or number or portion of spikes in a given timeframe), a relativevalue (e.g., as compared with the pre-treatment blood pressure of thepatient or as a comparison between a plurality of tested stimulationpatterns), or both. The target blood pressure value may be a bloodpressure value (e.g., measured in mmHg) and/or a value associated with aformula calculated to match a blood pressure measurement of astimulation pattern, etc. This target blood pressure value may be setbefore, during, and/or after the other method steps and it may also beamended, for example, if not reached by any tested simulation pattern.

Step 602 may include delivery of one or more stimulation patterns,including a first stimulation pattern, to one or more chambers of apatient's heart. The first stimulation pattern may be a genericstimulation pattern or the first stimulation pattern may already beselected to match a given patient (e.g., when implanting a replacementdevice). The first stimulation pattern may include at least onestimulation setting configured to reduce or prevent atrial kick in atleast one ventricle and/or to control atrial pressure and/or stretch,for a first time interval.

Step 603 may include sensing one or more parameters before, during,and/or after the delivery of each of one or more stimulation patterns(step 602). The sensed parameter(s) may include sensing atrial pressureto assess an overlap between the maximum of atrial pressure due tocontraction and the maximum of atrial pressure that is due toventricular contraction. The sensed parameter(s) may include sensingatrial pressure as a result of delivery of each of one or morestimulation patterns (step 602), to assess a pressure obtained with thestimulation and optionally compare it with one or more of pressuresobtained with a different stimulation or without stimulation.Optionally, the parameter(s) may include a blood pressure value or ablood pressure related parameter (e.g., a change in blood pressure). Insome embodiments, the sensed parameter(s) may include informationrelating to the timing and/or extent of closure and/or opening of an AVvalve. In some embodiments, the sensed parameter(s) may includeinformation relating to the timing and/or rate of blood flow between anatrium and ventricle of the heart. In some embodiments, the sensedparameter(s) may include sensing pressure within a heart chamber (e.g.,an atria and/or ventricle). In some embodiments, sensing of a patient'sAV valve status, or position, (i.e., opened or closed) may includesensing of heart sounds, for example, using audio sensors. In someembodiments, sensing of a patient's AV valve status may include Dopplersensing and/or imaging of cardiac movement. In some embodiments, thepatient's AV valve status may be sensed by a blood flow sensor.

In some embodiments, sensing of blood flow may be performed by one ormore implanted sensors in one or more cardiac chambers. For example, oneor more pressure sensors may be placed in the right ventricle. In someembodiments, a plurality of pressure sensors may be placed in aplurality of chambers. Optionally, measurements of a plurality ofsensors may be combined. Optionally, pressure changes, trends ofpressure changes, and/or pressure change patterns may be used to provideinformation relating to blood flow. In some embodiments, comparingrelative changes between two or more sensors in different chambers maybe used.

When a stimulation pattern is delivered to a heart (step 602), the oneor more parameters may be measured at least once during delivery of thestimulation pattern or at a plurality of times or even continuously.Each stimulation pattern may be delivered more than once.

Step 604 may include analyzing the sensed parameter(s). In someembodiments, once at least one stimulation pattern is delivered andcorresponding parameter(s) are sensed, analysis may be performed (604).In embodiments in which multiple parameters are sensed, step 604 mayinclude the following: comparing sensed parameter values to a target;comparing sensed parameters between two or more stimulation patterns;comparing calculated values (e.g., the k constant) relating to two ormore stimulation patterns; and comparing additional sensed parametersbetween two or more stimulation patterns. In some embodiments, this lastfunction may be performed to determine and select which stimulationpattern yields a higher ejection fraction, stroke volume, cardiacoutput, and/or a lower battery use.

Step 605 may include setting a pacing (stimulation) pattern. When morethan one parameter is sensed, the stimulation pattern used in step 605may be selected based on the plurality of parameters, a plurality oftarget values, and/or a plurality of target ranges.

In some embodiments, the steps shown in FIG. 8 may be performed in theorder shown by the arrows in FIG. 8. In other embodiments, the steps maybe performed in another order. For example, step 602 may be performedbefore setting a target blood pressure value in accordance with step601. In some embodiments, a stimulation pattern may be set to beperformed indefinitely. In some embodiments, a stimulation pattern maybe set to be performed for a predetermined period of time. For example,in some embodiments, the stimulation pattern set during step 605 may beperformed for a predetermined period of time and then step 602, step603, and step 604 may be repeated to determine how another stimulationpattern affects the patient's blood pressure. Then, based on theanalysis performed in step 604, step 605 may also be repeated.

In some embodiments, method 600 may include a step of adjusting a firststimulation pattern, thus making the first stimulation pattern into asecond stimulation pattern. In some embodiments, step 605 of setting astimulation pattern may include adjusting a stimulation pattern. Forexample, step 605 may include adjusting a parameter of a firststimulation setting, e.g., the time interval from step 602. In anotherembodiment, step 605 may include adjusting a parameter of a firststimulation setting configured to reduce or prevent the atrial kick inat least one ventricle and/or to control atrial pressure and/or stretch.In some embodiments, step 605 may include adjusting first stimulationpattern to be a second stimulation pattern configured to cause areduction in blood pressure by at least a predetermined amount. In someembodiments, the predetermined amount may include, for example, about 8mmHg to about 30 mmHg. In some embodiments, the predetermined amount maybe at least 4% of a patient's pretreatment blood pressure. For example,the predetermined amount may be about 4% of a patient's pretreatmentblood pressure to about 30% of a patient's pretreatment blood pressure.

In some embodiments, step 605 may include adjusting the stimulationpattern to be a stimulation pattern configured to cause an immediatereduction in blood pressure by at least a predetermined amount. Forexample, in some embodiments, step 605 may include adjusting thestimulation pattern to be a stimulation pattern configured to cause areduction in blood pressure by at least a predetermined amount withinabout 3 sec from an application of electricity to the heart. In someembodiments, step 605 may include adjusting the stimulation pattern tobe a stimulation pattern configured to cause a reduction in bloodpressure by at least a predetermined amount within at least 5 heartbeatsof the applied electricity. In some embodiments, the reduction in bloodpressure resulting from a stimulation pattern set during step 605 mayoccur within 1-3 sec of the application of electricity to the heart orwithin 1, 3, or 5 heartbeats of the application of electricity to theheart.

In some embodiments, the reduction in blood pressure resulting from astimulation pattern set during step 605 may be such that a patient'saverage blood pressure at rest is at least 8 mmHg below the patient'sinitial blood pressure at rest. In some embodiments, the reduction inblood pressure resulting from a stimulation pattern set during step 605may be maintained for at least 1 minute. In some embodiments, thereduction in blood pressure resulting from a stimulation pattern setduring step 605 may be maintained for at least 5 minutes. In someembodiments, the blood pressure may reach a minimal blood pressure valuewithin less than 5 heartbeats from the beginning of stimulation. Forexample, step 605 may include adjusting a first stimulation pattern tobe a second stimulation pattern configured to cause a reduction in bloodpressure. In some embodiments, step 605 may include adjusting the firststimulation pattern to a second stimulation pattern configured to causea reduction in blood pressure for a predetermined time interval. Forexample, the predetermined time interval may include at least 1 minuteor at least 5 minutes.

In some embodiments, the second stimulation pattern may be configured tomaintain a blood pressure that does not exceed a predetermined averagevalue during the predetermined interval by more than a predetermineddegree. For example, the predetermined degree may be a difference ofabout 20 mmHg or less. In some embodiments, the predetermined degree maybe a difference of about 1 mmHg to about 8 mmHg. In some embodiments, apatient's blood pressure may exceed a predetermined average value forsome heartbeats, but the patient's average blood pressure may not exceedthe predetermined average value.

In some embodiments, the second stimulation pattern may include a secondstimulation setting configured to reduce or prevent the atrial kick inat least one ventricle and/or to control atrial pressure and/or stretch.The second stimulation setting may be based upon at least one bloodpressure variation parameter calculated from an input data sensed duringapplication of the first stimulation pattern.

In some embodiments, the second stimulation pattern may be configured toreduce or limit the magnitude of spikes in blood pressure betweenstimulation pulses. In some embodiments, the spikes in blood pressurebetween stimulation pulses may be reduced to a percentage of a baselineblood pressure value. For example, the second stimulation pattern may beconfigured to prevent more than an 80% increase in blood pressurebetween pulses. In other words, the second stimulation pattern may beconfigured to prevent the blood pressure from spiking more than about80% between pulses. In some embodiments, the second stimulation patternmay be configured to prevent more than a 40% increase in blood pressurebetween pulses. In some embodiments, the second stimulation pattern maybe configured to prevent a blood pressure spike of more than about 10mmHg to about 30 mmHg between pulses. For example, in some embodiments,the second stimulation pattern may be configured to prevent a bloodpressure spike of more than 20 mmHg between pulses.

In some embodiments, the second stimulation pattern may comprisemultiple stimulation pulses. At least one stimulation pulse of themultiple stimulation pulses may have a first stimulation settingconfigured to reduce atrial kick in at least one ventricle and/or tocontrol atrial pressure and/or stretch. At least one stimulation pulseof the multiple stimulation pulses may have a second stimulation settingconfigured to reduce the baroreflex response to the reduction in atrialkick or to the control of atrial stretch such that the increase in bloodpressure values occurring between stimulation pulses is limited to apredetermined value. In some embodiments, the second stimulation settingmay be configured to increase blood pressure for about 1 heartbeat to 5heartbeats to invoke negation of the baroreflex response. In someembodiments, the second stimulation pattern may include multiplestimulation pulses having the first stimulation setting and multiplestimulation pulses having the second stimulation setting. In suchembodiments, between about 1% of the multiple stimulation pulses and 40%of the multiple stimulation pulses of the stimulation pattern may havethe second stimulation setting. In some embodiments, the secondstimulation pattern may include multiple stimulation pulses having thefirst stimulation setting and multiple stimulation pulses having thesecond stimulation setting. In such embodiments, between about 1 of themultiple stimulation pulses and 40% of the multiple stimulation pulsesof the stimulation pattern may have the second stimulation setting. Insome embodiments, the stimulation pattern may include a ratio ofstimulation pulses having the first setting to the stimulation pulseshaving the second setting based on a ratio of time constants of theresponse to increase and decrease in blood pressure. For example, theratio of stimulation pulses having the first setting to the stimulationpulses having the second setting may be based on a ratio of the timeconstants of the changes in blood pressure resulting from each of thefirst setting and the second setting. In some embodiments, the firststimulation setting may include a first AV delay and the secondstimulation setting may include a second AV delay, the first AV delaybeing shorter than the second AV delay. In some embodiments, the secondstimulation pattern may include multiple stimulation pulses having thefirst stimulation setting and one or more stimulation pulses having thesecond stimulation setting. In some embodiments, the second stimulationpattern may include a ratio of about 8 stimulation pulses to about 13stimulation pulses having the first setting to about 2 stimulationpulses to about 5 stimulation pulses having the second setting. In someembodiments, the second stimulation pattern may include at least onestimulation pulse having a stimulation setting configured to invoke ahormonal response from the patient's body. In some embodiments, thefirst stimulation pattern may include at least one stimulation pulsehaving a stimulation setting configured not to invoke a hormonalresponse from the patient's body. In some embodiments, the secondstimulation pattern may be applied before the first stimulation patternin a given sequence of stimulation patterns.

In some embodiments, method 600 may include alternating between two ormore stimulation patterns. For example, method 600 may includealternating between two to ten stimulation patterns.

In some embodiments, the blood pressure sensor and the controller may beconfigured to operate at least partially as a closed loop.

In some embodiments, method 600 may include the controller executing aplurality of stimulation patterns and receiving for each of thestimulation patterns a corresponding input data relating to a patient'sblood pressure during the stimulation. The plurality of stimulationpatterns may include at least two stimulation patterns each comprisingat least one stimulation pulse having a stimulation setting configuredto reduce or prevent the atrial kick in at least one ventricle and/or tocontrol atrial pressure and/or stretch. The at least two stimulationpatterns may differ from one another by the number of times or thelength of time the at least one stimulation pulse is provided insequence. The at least two stimulation patterns may differ from oneanother by the number of times or the length of time a predetermined AVdelay occurs in sequence. In some embodiments, the stimulation settingmay be identical in each of the at least two stimulation patterns. Insome embodiments, the stimulation setting may include an identical AVdelay for each of the at least two stimulation patterns. In someembodiments, the at least two stimulation patterns may differ from oneanother by one or more stimulation settings included within each of theat least two stimulation patterns.

In some embodiments, method 600 may include the controller calculatingfor each of the plurality of stimulation patterns at least one bloodpressure variation parameter relating to the input data. Method 600 mayinclude the controller adjusting the stimulation pattern according tothe blood pressure variation parameter. In some embodiments, method 600may include the controller adjusting the stimulation pattern to be thestimulation pattern with the best blood pressure variation parameter.For example, the best blood pressure variation parameter may include theblood pressure variation parameter that displays the lowest degree ofbaroreflex. The best blood pressure variation parameter may include theblood pressure variation parameter that displays a baroreflex within apredetermined range.

In some embodiments, the second stimulation pattern may include at leastone stimulation pulse having a stimulation setting configured to invokea hormonal response from the patient's body, while in some embodiments,the first stimulation pattern may include at least one stimulation pulsehaving a stimulation setting configured not to invoke a hormonalresponse from the patient's body.

In some embodiments, the plurality of stimulation patterns may include afirst stimulation pattern and a second stimulation pattern executedafter the first stimulation pattern. The second stimulation pattern mayhave at least one stimulation setting that was set based on an algorithmusing blood pressure variation parameters relating to the input data ofthe first stimulation pattern.

Embodiments of Systems for Reducing Blood Pressure

FIG. 9 schematically depicts an exemplary system 700 for reducing bloodpressure according to some embodiments. System 700 may be a device ormay comprise a plurality of devices, optionally associated by wire orwireless communication. The device(s) may have multiple componentsdisposed inside a housing and/or connected to the housing electronicallyand/or by wires. As shown in FIG. 9, a heart 701 is connected to asystem 700 by one or more stimulation electrodes 702. The stimulationelectrode(s) may be configured to stimulate at least one chamber of aheart of a patient with a stimulation pulse. In some embodiments,multiple electrode(s) 702 may each be positioned in a different chamberof the heart. For example, one electrode may be positioned in an atriumand another electrode may be positioned in a ventricle. In someembodiments, multiple electrodes 702 may be positioned in a singlechamber. For example, two electrodes may be positioned in an atriumand/or two electrodes may be positioned in a ventricle. In someembodiments, one electrode may be positioned in a first chamber andmultiple electrodes may be positioned in a second chamber.

In the present embodiment, the electrode(s) 702 may include typicalcardiac pacemaker leads, such as the Medtronic Capsure® pacing leads.These leads are used to connect the heart 701 to system 700. The pacingleads may be constructed with an industry standard IS-1 BI connector atone end (reference standard ISO 5148-3:2013), electrodes at the otherend, and an insulated conductor system between them. In someembodiments, the IS-1 BI connector is constructed using stainless steelfor the two electrode contacts and silicone as an insulating material.Some embodiments may use polyurethane as an insulating material.

Stimulation of one or more cardiac chambers may be accomplished byplacing a voltage between the two electrodes of the atrial orventricular cardiac pacing leads described above. The stimulationcircuit uses a network of transistors (e.g., MOSFETS) to charge acapacitor to a specific programmable voltage, such as 2.0V, and thencontrol its connection to the electrodes for a fixed period ofprogrammable time, such as 0.5 ms. The same network may also manage adischarge of any residual charge that may be accumulated on theelectrodes after stimulation is complete. The same network may controlthe type of stimulation applied, such as bipolar (between the twoelectrodes) or unipolar (between one electrode and the stimulatorhousing).

One or more electrodes may be placed in contact with one or bothventricles and/or one or both atria, as known in the art. Suchelectrodes may be used to sense and/or deliver stimuli to the respectivecardiac chamber(s). For example, pacing electrodes can be introduced toboth ventricles, with one electrode implanted into the right ventricleand an additional electrode placed on the left ventricle through thecoronary sinus, and with the system 700 including means to generatebiventricular stimulation of both ventricles in order to reducedyssynchrony caused by ventricular stimulation.

System 700 may include a controller 703. System 700 may be an electricalstimulator including a power source 704 (e.g., a battery as known in theart of electrical stimulators). Controller 703 and/or electrode(s) 702may draw power from power source 704.

Optionally, the electrical stimulator of system 700 is constructed of ahermetically sealed housing and a header. The housing may be constructedof titanium or any other biocompatible material, and may contain a powersource 704, electronics, and a telemetry coil or communication module707 for communication with an external device. The power source 704 maybe an implantable grade, hermetically sealed, primary battery. Thebattery chemistry may be lithium-iodine. Other embodiments may uselarger or smaller batteries. Other embodiments may use rechargeablebatteries such as Li-ion rechargeable batteries. The electronics in someembodiments may be constructed of standard off-the-shelf electronics(e.g., transistors and diodes) and/or custom electronics (e.g., ASIC).

In order to detect the onset of atrial excitation and/or ventricularexcitation, one or more sensing electrodes may be implanted at or near asite of interest in the heart. These sensing electrodes may be the sameelectrodes used for delivering pulses to the heart or dedicated sensingelectrodes. The electrical activity may be band-pass filtered to removeunwanted noise and may conform to an international standard for cardiacpacemakers (reference EN45502-2-1:2003), with programmable cutofffrequencies. An electrical circuit may be used to amplify the electricalsignals generated by a propagating activation of the cardiac chamber andto determine the onset of activation once the electrical signals fulfillspecified criteria, for example, crossing of a predefined threshold. Thesignal may, for example, be amplified, with programmable gains, and thenpassed to a comparator for threshold detection, with programmabledetection thresholds in steps of 0.2 mV (atrial) and 0.4 mV (ventricle).These means of detecting excitation may introduce a delay between theactual onset of activation in the chamber and its detection, since thedetecting electrodes may be away from the origin of excitation and thetime it takes for the signal to fulfill the detection criteria might notbe negligible and may be in the range of 5 to 50 ms or even more. Insuch cases, the timing of the onset of excitation may be estimated basedon the timing of a sensed excitation, and the delivery of stimulationpulses would be calculated to compensate for this delay.

Optionally, the controller 703 interfaces with an accelerometer tomeasure patient activity level. This patient activity level may be usedto adjust the pacing rate and/or BPR settings and/or the stimulationpattern based upon the patient's needs. Activity level may also be usedto control a desired level of effect on blood pressure. For example,reduction in blood pressure may be reduced at high levels of activity toenable better performance when an increase in blood pressure isrequired. Optionally, when a patient is inactive (e.g., when sleeping)blood pressure may reduce naturally, in which case pacing may beadjusted in order to avoid reducing blood pressure below a desiredthreshold. Activity level may also be used to adjust settings based onbaroreflex to allow better response when needed. The sensor may be, forexample, a piezoelectric sensor. Other embodiments may use a MEMS-basedaccelerometer sensor. Other embodiments may use a minute ventilationsensor, optionally in combination with an accelerometer.

Controller 703 may be configured to deliver electricity to the heart 701via one or more electrodes 702. Controller 703 may be configured toexecute a stimulation pattern of stimulation pulses according to anyembodiment of this disclosure. In some embodiments, the stimulationpulses may be delivered to at least a ventricle of the heart. In someembodiments, the stimulation pattern may include a first stimulationsetting and a second stimulation setting different from the firststimulation setting, with the first stimulation setting and the secondsetting configured to reduce or prevent the atrial kick and/or tocontrol atrial pressure and/or stretch. In some embodiments, the firststimulation setting has a different AV delay than the second stimulationsetting. In some embodiments, the first stimulation setting and/or thesecond stimulation setting may be configured such that an atrialpressure resulting from atrial contraction of an atrium overlaps in timea passive pressure build-up of the atrium, thereby providing an atrialpressure of the atrium that is a combination of the atrial pressureresulting from atrial contraction and the passive pressure build-up andis higher than an atrial pressure of the atrium would be without thestimulation. In some embodiments, the first stimulation setting and/orthe second stimulation setting may be configured such that maximumatrial stretch is at a value that is about equal to or lower than themaximum atrial stretch of the same heart when not receiving stimulation.In some embodiments, the first stimulation setting and/or secondstimulation setting are configured to cause an atrium to be at maximumcontraction force when the AV valve is open. In some embodiments, thefirst stimulation setting and/or second stimulation setting areconfigured to alter the mechanics of at least one atrial contractionsuch that the mechanics of the at least one atrial contraction aredifferent from the mechanics of a previous natural atrial contraction.In some embodiments, the first stimulation setting and/or secondstimulation setting are configured to reduce the force of at least oneatrial contraction. In some embodiments, the first stimulation settingand/or second stimulation setting are configured to prevent at least oneatrial contraction.

In some embodiments, the controller 703 may be configured to deliver avariety of different AV delays. The controller 703 may be configured tosense when the atrial contraction or excitation occurs (as describedherein) and then deliver ventricular stimulation a fixed interval afterthat or before a future anticipated atrial excitation or contraction.The interval may be programmable. The controller 703 may also beconfigured to stimulate the atrium and then deliver ventricularstimulation at a fixed interval after that, which may also beprogrammable. The programmable interval may, for example, be changedbetween 2 ms and 70 ms to accommodate a desired therapeutic effect oreven provide a negative AV delay of up to −50 ms.

In some embodiments, controller 703 may be configured to repeat astimulation pattern multiple times. For example, controller 703 mayrepeat a stimulation pattern twice. In another embodiment, controller703 may be configured to repeat a stimulation pattern at least twice ina period of an hour. The stimulation pattern repeated by controller 703may include any type of stimulation pattern. For example, thestimulation pattern may include a stimulation setting configured toreduce or prevent the atrial kick in at least one ventricle and/or tocontrol atrial pressure and/or stretch. In another embodiment, thestimulation pattern may include two different stimulation settings eachconfigured to reduce or prevent the atrial kick in at least oneventricle and/or to control atrial pressure and/or stretch. These twostimulation settings may differ by one or more parameters, for example,by AV delay.

In some embodiments, controller 703 may be configured to execute one ormore consecutive stimulation patterns for a predetermined time interval.For example, in some embodiments, the time interval may be 10 minutes orlonger. In another embodiment, the time interval may be 30 minutes orlonger, one hour or longer, or 24 hours or longer. In some embodiments,the time interval may be a period of months, such as one month to oneyear. In some embodiments, the time interval may be longer than oneyear. In some embodiments, the one or more consecutive stimulationpatterns may include a first stimulation setting configured to reduce orprevent the atrial kick in at least one ventricle and/or to controlatrial pressure and/or stretch, for a portion of the time interval. Forexample, the one or more consecutive stimulation patterns may include afirst stimulation setting configured to reduce or prevent the atrialkick in at least one ventricle and/or to control atrial pressure and/orstretch, for about 50% of a time interval to about 100% of the timeinterval. In another embodiment, the one or more consecutive stimulationpatterns may include a first stimulation setting configured to reduce orprevent the atrial kick in at least one ventricle and/or to controlatrial pressure and/or stretch, for about 50% of a time interval toabout 85% of the time interval. In some embodiments, the one or moreconsecutive stimulation patterns may include a second stimulationsetting having a longer AV delay than the first stimulation setting forat least one heartbeat during the time interval. In some embodiments,the one or more consecutive stimulation patterns may include a secondstimulation setting and/or a third stimulation setting. The secondstimulation setting and/or third stimulation setting may each bedifferent from the first stimulation setting. In some embodiments, thesecond stimulation setting and/or third stimulation setting may each beconfigured to reduce or prevent the atrial kick in at least oneventricle and/or to control atrial pressure and/or stretch. In someembodiments, the second stimulation setting and/or third stimulationsetting may each be configured not to reduce or prevent the atrial kickin at least one ventricle and/or not to control atrial pressure and/orstretch. In some embodiments, the second stimulation setting and/orthird stimulation setting may include about 0% of a time interval toabout 50% of the time interval. In some embodiments, the secondstimulation setting and/or third stimulation setting may include about0% of a time interval to about 30% of the time interval. In someembodiments, the second stimulation setting and/or third stimulationsetting may include about 0% of a time interval to about 20% of the timeinterval. In some embodiments, the second stimulation setting and/orthird stimulation setting may include about 5% of a time interval toabout 20% of the time interval.

Blood pressure is known to vary in a circadian manner, and in some casesabnormally high blood pressure is prevalent only or mostly during partof a 24-hour period (e.g., nighttime or daytime or parts thereof).Additionally, blood pressure is known to vary according to physicalactivity, with an active person having a higher blood pressure than thesame person at rest. In some cases, it may thus be desired to controlthe delivery of treatment according to need, for example, by changingtherapy parameters or even withholding the delivery of cardiacstimulation to reduce blood pressure. In other words, at different timesof the day and/or when a patient is active or at rest, cardiacstimulation may be changed to adjust parameters of the stimulation, ormay be simply turned on/off. Optionally, the delivery of suchstimulation may be controlled according to the time of day and adjustedto a patient's circadian BP rhythm.

For example, FIG. 21 shows the systolic BP of an untreated patientduring a 24-hour period of monitoring. An hourly average is presented.As shown, the patient's BP was abnormally high only during the day(circa 10 a.m. to 6 p.m.). In such types of cases, it may be preferredto set a device to deliver pulses configured to reduce atrial kickand/or to provide AC stimulation only during the time of day when BP isexpected to be abnormally high (i.e., when there is a need or where aneed is expected).

Another example is shown in FIG. 22. Here a patient's untreated bloodpressure (represented in FIG. 22 by the line with “x” data points) wasshown to be abnormally high during the night (after 2 p.m. and before 7a.m.). An increase in BP during the day was within normal range and maybe attributed to an increase in patient activity. Optionally, it may beassumed that this patient would be in need of treatment only during thenight, and a device may be set to deliver stimulation accordingly.Optionally it may be assumed that the patient does not need treatmentduring the day, and a device may be set such that even if an increase inblood pressure is measured during the day, such increase should notelicit the delivery of treatment to reduce blood pressure. Optionally,the device may be set not to measure blood pressure during the day. Inthe example shown in FIG. 22, the patient was then treated with a bloodpressure reducing pulse having the following setting: pacing both anatrium and ventricle with an AV delay of 15 ms for 10 heartbeatsfollowed by pacing the atria and the ventricle for 3 heartbeats with anAV delay of 40 ms. The therapy was delivered every day starting at 3p.m. and lasting 13 hours. The resulting BP was plotted (represented inFIG. 22 by the with circle data points), and as can be seen, BP waswithin normal range essentially throughout the day and displayed muchless variation than it did during pre-treatment (under treatment, BPvaried by no more than about 30 mmHg, while the untreated range variedby more than 40 mmHg).

In some embodiments, an intrinsic (without stimulation) blood pressureprofile of a patient is first determined, and based on that intrinsicprofile, stimulation parameters that generate a desired reduction inblood pressure are then determined accordingly. FIG. 22 illustrates oneexample of such an approach. In some embodiments, blood pressure ismeasured continuously or intermittently during operation of the device,and the stimulation parameters that generate a desired reduction inblood pressure are then determined accordingly.

In some embodiments, controller 703 may be configured to execute one ormore consecutive stimulation patterns including a sequence of 10-60stimulation pulses having a first stimulation setting configured toreduce or prevent the atrial kick in at least one ventricle and/or tocontrol atrial pressure and/or stretch. In some embodiments, controller703 may be configured to execute one or more consecutive stimulationpatterns including a sequence of 1-10 heartbeats embedded within the10-60 stimulation pulses and the sequence of 1-10 heartbeats may have alonger AV delay than the first stimulation setting. For example, the10-60 stimulation pulses may include 5 stimulation pulses having thefirst stimulation setting, followed by one heartbeat having a longer AVdelay than the first stimulation setting, followed by 50 stimulationpulses having the first stimulation setting. The sequence of 1-10heartbeats may include at least one stimulation pulse having a firststimulation setting configured to reduce or prevent the atrial kick inat least one ventricle and/or to control atrial pressure and/or stretch.The sequence of 1-10 heartbeats may include a natural AV delay. Thesequence of 1-10 heartbeats may occur without stimulation.

System 700 may further comprise one or more sensors 705. In someembodiments, such sensor(s) 705 may include one or more sensingelectrode(s) for sensing electrical activity of the heart. In someembodiments, one or more sensing electrode(s) may include one or morestimulation electrode(s) 702. In some embodiments, sensor(s) 705 mayinclude one or more blood pressure sensors (implantable and/orexternal). In some embodiments, one or more sensors 705 may include oneor more pressure sensors implanted in the heart (e.g., in the atriaand/or ventricle). In some embodiments, sensor(s) 705 may include one ormore blood flow sensors (implantable and/or external). For example, oneor more sensors 705 may include ultrasound sensing of blood flow throughthe AV valve. In some embodiments, sensor(s) 705 may include one or moresensors configured to monitor the timing of closure of the AV valve. Oneor more of these sensors may be configured to operate as a closed loopwith the controller.

Information from sensor(s) 705 may be provided to controller 703 by anyform of communication, including wired communication and/or wirelesscommunication. Optionally, system 700 may comprise one or morecommunication modules 707 for receiving and/or transmitting informationbetween system components and/or to devices that are external to thesystem. In some embodiments, controller 703 may be configured to receiveinput data relating to the patient's blood pressure. For example, theinput data relating to the patient's blood pressure may include dataindicative of BP measured at one or more points in time or of avariation in BP (e.g., a degree of change and/or a rate of change or afunction describing the change of blood pressure over time) and/orstatistical data relating to BP or variation in BP, maximum and/orminimum BP values

Optionally, system 700 may comprise one or more user interfaces 708 forproviding information and/or for allowing input of information.Providing information may include, for example, a display of operationalinformation relating to the system and/or data that was recorded by thesystem and/or received by the system during operation. This may includesensed parameter(s) and/or a relation between sensed parameter(s) andoperational information (such as stimulation pattern settings and/orrelative timing between delivery of a given pace and sensedinformation).

Optionally, user interface 708 may be comprised of a commerciallyavailable laptop computer (e.g., Windows®-based computer) running asoftware application. The software application may serve to generateorders to be delivered to an interface that is, in turn, connected to ahand-held wand that contains a telemetry circuit for communication withthe implantable stimulator. The orders sent to the wand may be used toset stimulation parameters and/or to retrieve device diagnostics, devicedata, cardiac data, and real-time cardiac sensing. The interface alsoallows for connection of a 3-lead ECG and this data is displayed on thelaptop computer screen by the software application. Other embodimentsmay not include the 3-lead ECG circuitry or may include 12-lead ECGcircuitry. Other embodiments may incorporate the functionality of thewand, interface, and laptop computer into a dedicated piece of hardwarethat performs all three functions. Other embodiments may also addprinting capability to the user interface 708.

In some embodiments, interface(s) 708 may be configured such that a user(e.g., medical practitioner) may provide a set of control instructionsto the system (e.g., target values and/or ranges and/or otherlimitations or instructions). Optionally, interface(s) 708 may allow auser to input data from one or more sensors 705 (e.g., the results of amanual blood pressure measurement and/or results of an ultrasoundmonitor).

Optionally, the one or more user interfaces 708 may allow a user toselect a stimulation pattern (for example, from a set of stimulationpatterns stored in system 700) or impose constraints on the settingand/or selecting of a stimulation pattern.

Optionally, system 700 may comprise one or more processors 706.Processor(s) may be configured to process sensed parameters fromsensor(s) 705 and/or input data from user interface(s) 708 to select astimulation pattern for delivery by system 700. Optionally, processor(s)706 may be configured to analyze sensed parameters and extractinformation and/or formula constants to be used in the selection and/orevaluation of stimulation patterns.

One or more components of system 700 or portions of such components maybe implanted in the patient, while some components of system 700 orportions of such components may be external to the patient. When somecomponents (or component parts) are implanted and others are not,communication between the components may take place by wired and/orwireless means, essentially as known in the art. For example, some orall functions of both controller 703 and/or processor 706 may beperformed outside the body. Having some components of system 700external to the patient's body may assist in reducing the size and/orenergy requirements of an implanted device, and/or in the enhancement ofthe system's computation capabilities.

System 700 may include additional functions relating to control of heartfunction and overall cardiovascular system performance. For example,system 700 may include one or more algorithms and/or electrodes toenable biventricular pacing or resynchronization therapy to reducedyssynchrony that may be caused by ventricular stimulation. In someembodiments, system 700 may include one or more algorithms to compensatefor a possible reduction in cardiac output. Such an algorithm that maychange heart rate in order to increase cardiac output or implement othermethods known in the art for controlling cardiac output. In someembodiments, system 700 may include rate response algorithms to affectchanges in heart rate as a response to certain circumstances. Forexample, system 700 may include rate response algorithms to affectchanges in heart rate as a response to changes in level of exercise,ventilation activity, and/or oxygen consumption. In some embodiments,system 700 may include a sensor that detects activity and the algorithmmay turn off stimulation while a patient is exercising such that apatient's blood pressure is not reduced. In some embodiments, system 700may include a real-time clock. Such a clock may be used to control thetiming of the stimulation. For example, system 700 may include analgorithm that turns stimulation on and off depending upon the time ofday. This type of algorithm may be used to prevent hypotension duringthe night when a patient is sleeping.

In some embodiments, a kit including one or more components of system700 and a set of instructions for adjusting the stimulation patternbased on input relating to a patient's blood pressure may be provided.

Some embodiments may provide a system for reducing blood pressureconfigured to deliver stimulation at a rate higher than the naturalheart rate based on sensed natural heart rate or natural excitation. Forexample, the system may be configured to sense the natural excitationbetween delivery of stimulation pulses and if a natural activity issensed, the system may be configured to inhibit the delivery of thestimulation pulse to the chamber. If in a given time frame the amount ofsensed activations exceeds a threshold, the natural heart rate may beregarded as higher than the rate of delivery of the stimulation pulses,in which case the rate of delivery may be increased, e.g., toaccommodate increased heart rate of a patient. On the other hand, if ina given time frame the amount of sensed activations is lower than athreshold (this threshold may be 0), the natural heartbeat may beregarded as lower than the rate of delivery of the stimulation pulses,in which case the rate of delivery may be reduced, e.g., to avoid overexcitation of a patient's heart. To achieve this effect, according toone embodiment, a system for reducing blood pressure may include asensor for sensing an excitation rate of at least one of an atrium and aventricle of a patient's heart, a stimulation circuit configured todeliver stimulation pulses to an atrium and a ventricle, and a processorcircuit coupled to the stimulation circuit. The processor circuit may beconfigured to detect the patient's heart rate based on the sensing andoperate in an operating mode in which a stimulation pulse is provided toeach of the at least one of an atrium and a ventricle. The stimulationpulse may be delivered at a rate that is higher than the sensedexcitation rate and may be configured to stimulate the ventricle at atime between about 50 ms before and about 70 ms after stimulation of theatrium.

Some embodiments may provide a system for reducing blood pressure basedon a predicted next atrial contraction. For example, a system forreducing blood pressure may include a sensor for sensing an excitationrate of at least one of an atrium and a ventricle, a stimulation circuitconfigured to deliver a stimulation pulse to at least one of an atriumand a ventricle, and a processor circuit coupled to the stimulationcircuit. The processor circuit may be configured to operate in anoperating mode in which a timing of a next atrial excitation ispredicted based on the sensed excitation rate of the previous atrialexcitations, and at least one ventricle is stimulated at a time betweenabout 50 ms before and about 10 ms after the predicted next atrialexcitation. The predicted timing may be based on the time intervalbetween the two previous sensed atrial excitations and on a functionthat will be based on previously sensed time intervals between atrialexcitations. The function may include the change in time interval, therate of change in time intervals, and/or detection of periodicvariations in time intervals (e.g., periodic variation due tobreathing).

Optionally, a sensor for sensing the excitation rate of at least one ofan atrium and a ventricle may comprise an electrode for sensing atrialexcitation.

In a further aspect, prediction of a next atrial contraction may bebased on a function of previous sensed excitations including rate ofchange of intervals and periodic variations.

In a further aspect, the timing of the predicted next atrial excitationmay be adjusted to reflect a delay between an atrial excitation and asensing of the atrial excitation.

In a further aspect, the system may further comprise an additionalsensor for sensing a parameter relating to cardiac activity and foradjusting the time at which the ventricle is stimulated accordingly. Theparameter may be a member of a group consisting of data relating toblood pressure, blood flow, AV valve status, and wall motion of theheart or a part thereof. The additional sensor may be selected from thegroup consisting of pressure sensors, impedance sensors, ultrasoundsensors, and/or one or more audio sensors and/or one or more blood flowsensors. The additional sensor may be implantable.

Reducing Atrial Kick

Some embodiments stem from the inventors realization that blood pressurecan be reduced by causing a closure of at least one AV valve during atleast part of an atrial contraction. This will reduce, or even prevent,the contribution of the contraction of the atria to the filling of theventricles, and thus reduce cardiac filling at the end of diastole andconsequently reduce blood pressure.

In some embodiments, at least part of an atrial contraction may occuragainst a closed AV valve. For example, in some embodiments, 40% or moreof an atrial contraction may occur against a closed AV valve. In someembodiments, at least 80% of an atrial contraction may occur against aclosed AV valve. For example the contraction may start approximately 20ms or less before the contraction of the ventricle or the excitation ofthe atria may occur 20 ms or less before the excitation of theventricle. In some embodiments, 100% of an atrial contraction may occuragainst a closed AV valve, in which case ventricle excitation is timedsuch that ventricle contraction will begin before the commencement ofatrial contraction. This may include exciting the ventricle before theonset of atrial excitation. The higher the percentage is of an atrialcontraction that occurs with the AV valve closed, the more the atrialkick is reduced. Stimulation of both the atrium and the ventricle mayprovide better control of the percentage of an atrial contractionoccurring against a closed valve. Various embodiments may be implementedto cause at least part of an atrial contraction to occur against aclosed valve. For example, the AV valve may be closed 70 ms or lessafter the onset of mechanical contraction of the atrium or 40 ms or lessafter the onset of mechanical contraction of the atrium or even 5 or 10ms or less after the onset of mechanical contraction of the atrium. Insome embodiments, the AV valve may be closed before the onset ofmechanical contraction of the atrium. For example, the AV valve may beclosed within 5 ms before the onset of the mechanical contraction of theatrium. In some embodiments, the AV valve may be closed at the same timeas the onset of the mechanical contraction. In some embodiments, the AVvalve may be closed after the onset of the mechanical contraction of theatrium. For example, the AV valve may be closed within 5 ms after theonset of mechanical contraction of the atrium.

In some embodiments, the onset of a contraction of a chamber may besensed and a stimulation pulse may be timed relative to the sensed onsetof a contraction. The onset of contraction in a chamber is the start ofactive generation of contractile force in the chamber. The onset ofcontraction can be sensed by a rapid change in pressure that is notrelated to the flow of blood into the chamber. The onset of contractionmay also be sensed by measuring the movement of the walls of a cardiacchamber or measuring the reduction in volume of a chamber using anultrasound. These methods of sensing the onset of a contraction may havea delay between the actual onset of the contraction and the sensing ofan onset of contraction.

In some embodiments, the AV valve may be closed after the onset ofcontraction of at least one atrium. For example, the AV valve may beclosed about 0 ms to about 70 ms after the onset of contraction of atleast one atrium. In some embodiments, the AV valve may be closed about0 ms to about 40 ms after the onset of contraction of at least oneatrium. In some embodiments, the AV valve may be closed about 0 ms toabout 10 ms after the onset of contraction of at least one atrium. Insome embodiments, the AV valve may be closed about 0 ms to about 5 msafter the onset of contraction of at least one atrium.

Typically, an atrial contraction may begin about 40 ms to about 100 msafter the onset of atrial excitation. In some embodiments, the AV valvemay be closed after the onset of atrial excitation. For example, the AVvalve may be closed about 40 ms to about 170 ms after the onset ofatrial excitation. For example, the AV valve may be closed about 40 msto about 110 ms after the onset of atrial excitation. In anotherembodiment, the AV valve may be closed about 40 ms to about 80 ms afterthe onset of atrial excitation. For example, the AV valve may be closedabout 40 ms to about 75 ms after the onset of atrial excitation. Forexample, the AV valve may be closed about 40 ms to about 50 ms after theonset of atrial excitation.

In some embodiments, the onset of excitation in a chamber may be sensedand a stimulation pulse may be timed relative to the sensed onset ofexcitation. The onset of excitation is the initiation of a propagatingaction potential through a chamber. The onset of excitation may besensed by sensing the local electrical activity of a chamber using asensing electrode connected to an amplifier. The onset of excitation canalso be detected by electrocardiography.

In some embodiments, methods of sensing the onset of excitation may havea delay between the actual onset of the excitation and the sensing of anonset of excitation. The timing of a sensed atrial excitation may bedetermined by taking into account the delay between actual onset ofexcitation and the sensing thereof. For example, if a sensing delay isestimated to be 20-40 ms, and stimulation pulses are to be delivered0-70 ms after onset of atrial excitation, a system may be set to deliverpulses between 40 ms before the next anticipated sensing event to 30 msafter the next anticipated sensing event or 30 ms after the next sensingevent. Likewise, if the stimulation pulses are to be delivered to theventricle 0-50 ms before onset of atrial excitation, assuming the same20-40 ms sensing delay, a system may be set to deliver pulses between 40ms before the next anticipated sensing event to 90 ms before the nextanticipated sensing event. Sensing delays may be due to one or more of adistance between the site of onset of excitation and a sensingelectrode, the level of the electrical signal, characteristics of thesensing circuit, and the threshold set of a sensing event. The delay mayinclude, for example, the duration of the signal propagation from theorigin of excitation to the electrode location, the duration related tothe frequency response of the sensing circuit, and/or the durationnecessary for the signal propagation energy to reach a level detectableby a sensing circuit. The delay may be significant and can range, forexample, between about 5 ms to about 100 ms. One approach for estimatingthe delay is to use the time difference between an AV delay measuredwhen both atrium and ventricle are sensed and the AV delay when theatrium is paced and the ventricle is sensed. Other approaches may usecalculation of the amplifier response time based on the set threshold,signal strength, and frequency content. Other approaches may includemodifying the delay used with atrial sensing until the effect on bloodpressure is the same as the effect obtained by pacing both atrium andventricle with the desired AV delay.

In some embodiments, the AV valve may be closed before the onset ofexcitation or contraction of at least one atrium. For example, the AVvalve may be closed within about 0 ms to about 5 ms before the onset ofexcitation or contraction of at least one atrium. In some embodiments,the AV valve may be closed at the same time as the onset of excitationor contraction of at least one atrium.

In some embodiments, direct mechanical control of AV valve closure maybe performed. In such embodiments, a mechanical device or a portionthereof may be implanted in the patient, and operated to cause theclosing of a valve between the atrium and ventricle. For example, anartificial valve may be implanted in the patient's heart and operated toclose mechanically in accordance with some embodiments. In suchembodiments, instead of or in addition to providing a stimulationpattern, the aforementioned closure of the AV valves may be accomplishedby controlling the functioning of the implanted valve.

In some embodiments, a shortened or even negative time interval betweenthe onset of atrial excitation and ventricular excitation is employed toreduce cardiac filling, thereby reducing blood pressure. As used herein,a negative time interval between the onsets of atrial excitation andventricular excitation means that in a single cardiac cycle, the onsetof excitation for the at least one ventricle occurs before the onset ofatrial excitation. In this case, atrial contraction may take place, atleast partially, against a closed AV valve, since the generated pressurein the ventricles may be greater than the pressure in the atria. A shorttime after the initiation of ventricular contraction, the pressure inthe ventricles may exceed the pressure in the atria and may result inthe passive closure of the valve. This closure of the valve may reduceor even obliterate the atrial kick and, in turn, reduce ventricularfilling. Consequently, the force of ventricular contraction may bereduced and blood pressure may drop.

The time between the start of excitation and the start of the mechanicalcontraction in each cardiac chamber is not fixed. Thus, the timing ofexcitation does not guarantee the same effect on the timing betweencontractions. However, in some embodiments, the timing betweenexcitations is used as a frame of reference for practical reasons. Theultimate purpose of controlling the timing of excitation is to controlthe timing of a contraction.

In some embodiments, a shortened or even negative time interval betweenthe onset of atrial contraction and ventricular contraction may beemployed to reduce cardiac filling, thereby reducing blood pressure. Inthis case, better control over the contribution of the atria may beobtained since the start of the contraction of the ventricle will resultwith the closure of the valve.

In some embodiments, 40% or more of an atrial contraction may occurduring ventricular systole. For example, the atrial contraction maystart approximately 60 ms or less before the contraction of theventricle, or the excitation of the atria may occur 60 ms or less beforethe excitation of the ventricle. In some embodiments 80% or more of anatrial contraction may occur during ventricular systole. For example,the contraction may start approximately 20 ms or less before thecontraction of the ventricle, or the excitation of the atria may occur20 ms or less before the excitation of the ventricle. In someembodiments, 100% of an atrial contraction may occur during ventricularsystole, in which case ventricle excitation is timed such that ventriclecontraction will begin before the commencement of atrial contraction.This may include exciting the ventricle before the onset of atrialexcitation.

Some embodiments provide a method for causing the contraction of atleast one ventricle of a heart, such that the at least one ventriclecontracts during or before the contraction of the corresponding atrium.One way to achieve this goal is by exciting the ventricle at a point intime between about 50 ms before to about 70 ms after the onset ofexcitation of the corresponding atrium. In some embodiments, the timeinterval between the onset of excitation of at least one ventricle andthe onset of excitation of the corresponding atrium may be zero. Inother words, the onset of excitation for the at least one ventricle mayoccur at the same time as the onset of excitation of the correspondingatrium. In some embodiments, the onset of excitation of the ventriclemay occur between about 0 ms to about 50 ms before the onset of atrialexcitation. In some embodiments, the onset of excitation of theventricle may occur at least 2 ms before to at least 2 ms after theonset of excitation of the at least one atrium. In some embodiments, theonset of excitation of the ventricle may occur at least 10 ms before toat least 10 ms after the onset of excitation of the at least one atrium.In some embodiments, the onset of excitation of the ventricle may occurat least 20 ms before to at least 20 ms after the onset of excitation ofthe at least one atrium. In some embodiments, the onset of excitation ofthe ventricle may occur at least 40 ms before to at least 40 ms afterthe onset of excitation of the at least one atrium.

In some embodiments, a method may comprise delivering a stimulationpulse from a stimulation circuit to at least one of an atrium and aventricle, and operating a processor circuit coupled to the stimulationcircuit to operate in an operating mode in which a ventricle isstimulated to cause ventricular excitation to commence between about 0ms and about 50 ms before the onset of atrial excitation in at least oneatrium, thereby reducing the ventricular filling volume from thepretreatment ventricular filling volume and reducing the patient's bloodpressure from the pretreatment blood pressure. In such embodiments,atrial excitation may be sensed to determine the onset of atrialexcitation. The time interval between the onset of atrial excitation andthe moment that atrial excitation is sensed may be known and used tocalculate the timing of the onset of atrial excitation. For example, ifit is known that atrial excitation is sensed 20 ms after the onset ofatrial excitation and the ventricle is to be stimulated 40 ms before theonset of atrial excitation, then the ventricle is to be stimulated 60 msbefore the anticipated sensing of atrial excitation. In otherembodiments, the method may comprise operating a processor circuitcoupled to the stimulation circuit to operate in an operating mode inwhich an atrium is stimulated to cause atrial excitation to commencebetween about 0 ms and about 50 ms after the onset of ventricularexcitation in at least one ventricle, thereby reducing the ventricularfilling volume from the pretreatment ventricular filling volume andreducing the patient's blood pressure from the pretreatment bloodpressure. For example, the processor circuit may be configured tooperate in an operating mode in which one or more excitatory pulses aredelivered to an atrium between about 0 ms and about 50 ms after one ormore excitatory pulses are provided to the patient's ventricle. In suchembodiments, the pacing may be timed without relying on sensing atrialexcitation. Optionally, in such embodiments, atrial excitation is sensedin order to confirm that one or more excitatory pulses are delivered toan atrium before a natural excitation takes place. Optionally, atrialexcitation is set to commence between about 0 ms and about 50 ms afterthe onset of ventricular excitation when the intrinsic atrial excitationrate is lower than the intrinsic ventricular excitation rate.

In some embodiments, a device may comprise a stimulation circuitconfigured to deliver a stimulation pulse to at least one of an atriumand a ventricle. The device may comprise a processor circuit coupled tothe stimulation circuit. In some embodiments, the processor circuit maybe configured to operate in an operating mode in which a ventricle isstimulated to cause ventricular excitation to commence between about 0ms and about 50 ms before the onset of atrial excitation in at least oneatrium, thereby reducing the ventricular filling volume from thepretreatment ventricular filling volume and reducing the patient's bloodpressure from the pretreatment blood pressure. In such embodiments,atrial excitation may be sensed to determine the onset of atrialexcitation. The time interval between the onset of atrial excitation andthe moment that atrial excitation is sensed may be known and used tocalculate the timing of the onset of atrial excitation. For example, ifit is known or estimated that atrial excitation is sensed 20 ms afterthe onset of atrial excitation and the ventricle is to be stimulated 40ms before the onset of atrial excitation, then the ventricle is to bestimulated 60 ms before the anticipated sensing of atrial excitation. Inother embodiments, the processor circuit may be configured to operate inan operating mode in which an atrium is stimulated to cause atrialexcitation to commence between about 0 ms and about 50 ms after theonset of ventricular excitation in at least one ventricle, therebyreducing the ventricular filling volume from the pretreatmentventricular filling volume and reducing the patient's blood pressurefrom the pretreatment blood pressure. For example, the processor circuitmay be configured to operate in an operating mode in which one or moreexcitatory pulses are delivered to an atrium between about 0 ms andabout 50 ms after one or more excitatory pulses are provided to thepatient's ventricle. In such embodiments, the pacing may be timedwithout relying on sensing atrial excitation. Optionally, in suchembodiments atrial excitation is sensed in order to confirm that one ormore excitatory pulses are delivered to an atrium before a naturalexcitation takes place. Optionally, atrial excitation is set to commencebetween about 0 ms and about 50 ms after the onset of ventricularexcitation when the intrinsic atrial excitation rate is lower than theintrinsic ventricular excitation rate.

FIGS. 10A and 10B depict a healthy anesthetized canine heart, showing anelectrocardiogram (ECG), left ventricle pressure (LVP) and arterial(blood) pressure (AP) traced over a period of time. In FIG. 10A, beforepoint 101, the heart was allowed to beat naturally, and the ECG, LVP,and AP were traced. At point 101, ventricular pacing commenced. Theventricle was paced 2 ms after the onset of atrial excitation. Thispacing caused an immediate change in the ECG, which was concomitant witha reduction of both LVP and AP. The pacing continued at a 2 ms timeinterval between the onset of atrial contractions and the onset ofventricular pacing until point 103 in FIG. 10B, where pacing ceased. Asseen, immediately upon cessation of pacing, the ECG, LVP, and BP allreturned essentially to the same values as before pacing.

FIGS. 11A and 11B show a hypertensive canine heart under a naturalheartbeat (FIG. 11A) and when paced at a time interval of 2 ms betweenthe onset of atrial contractions and ventricular pacing (FIG. 11B). Eachof these figures shows traces of an ECG, right ventricular pressure(RVP), a magnified portion of the RVP, and right atrial pressure (RAP)of the heart.

In FIG. 11A, the P wave and QRS of the natural heartbeat are clearlyseen. An increase in atrial pressure is seen following the P wave as aresult of atrial contraction. In the RVP trace, a sharp increase in RVPis seen following a QRS complex on the ECG. This is a manifestation ofventricular contraction. When observed at a higher magnification, thissharp increase in RVP is preceded by an earlier, smaller increase inRVP, which coincides with atrial contraction and a reduction in atrialpressure and is a result of blood emptying from the atrium into thechamber. This is the atrial kick. In FIG. 11B, where pacing is at a timeinterval of 2 ms, the P wave is essentially unnoticeable on the ECG, andan artifact of the electrical stimulator is discernible. The atrial kickin this case is not visible on the magnified trace of right ventricularpressure because the atrial contraction occurred at the same time oreven a little after the start of ventricular contraction.

In FIG. 12, a hypertensive canine heart was paced either at a timeinterval of 60 ms between the pacing of the atria and the pacing of theventricle (trace portions 105 and 107) or a time interval 120 ms ofbetween atrial and ventricular pacing (trace portion 109). The traceshows the ECG of the heart, left ventricular pressure (LVP), rightventricular pressure (RVP), a magnification of RVP, and right atrialpressure (RAP). As seen in trace portions of RVP magnified correspondingwith trace portions 105 and 107, the atrial kick during pacing at the 60ms time interval is very slight and the contraction of the ventriclebegins slightly after the peak of atrial contraction. In this case thecontribution of atrial kick to ventricular filling is markedly reducedbut not totally eliminated and, on the other end, the peak of atrialcontraction does not occur against a closed valve and atrial stretchdoes not increase. During pacing at a time interval of 120 ms, theatrial kick is clearly seen (portion 109 in trace RVP magnified), butthe start of the ventricular contraction and the closure of the AV valveoccur before the completion of atrial contraction, thereby slightlyreducing the contribution of the atrial kick to ventricular filling.

In FIG. 16, the heart of a hypertensive patient was paced with differentAV delays. This example shows the results obtained by pacing in both anatrium and a corresponding ventricle versus pacing only the ventriclebased on the sensed pulses in the atrium. During interval d-d′, atrialpulses were sensed and ventricular pulses were paced with an AV delay of2 ms. During interval e-e′, the atrium and ventricle were both pacedwith an AV delay of 2 ms. During interval f-f′, the atrium and theventricle were both paced with an AV delay of 40 ms. During intervalg-g′, the atrium and the ventricle were both paced with an AV delay of20 ms. During interval h-h′, the atrium and the ventricle were bothpaced with an AV delay of 80 ms. As shown in this example, whencomparing interval d-d′ with interval e-e′, the blood pressure isreduced more when the atrium is paced during interval e-e′ than whenatrial activity was just sensed. As also shown in this example, whencomparing interval e-e′, interval f-f′, interval g-g′, and intervalh-h′, the shorter AV delays caused more of a reduction in blood pressurethan the longer ones. For example, interval g-g′ (20 ms AV-delay) showsa higher blood pressure than interval e-e′ (2 ms AV-delay). As shownfrom the results of this example, the changes in blood pressure may becaused at least partially by the different AV delays, which result indifferent percentages of atrial contraction against a closed valve.

Exemplary Embodiments of Methods for Reducing Atrial Kick

An exemplary method 40 for reducing blood pressure is depictedschematically in FIG. 13. Method 40 may be performed by device 50 ofFIG. 14, described below. Accordingly, device 50 may be configured toperform any or all steps of method 40. Similarly, method 40 may includeany steps device 50 is configured to perform. For example, method 40 mayinclude any of the functions discussed above with respect to device 50.Method 40 may include any steps from method 600. Similarly, method 600may include any steps from method 40. Method 40 may include any stepsthat system 700 may be configured to perform. System 700 may beconfigured to perform any or all steps of method 40.

In some embodiments, method 40 may include a step 41 of atrialexcitation. In some embodiments, step 41 includes sensing an atrialexcitation. For example, step 41 may include sensing an intrinsic atrialexcitation. In some embodiments, step 41 includes triggering atrialexcitation. Method 40 may include a step 42 in which a time interval isapplied. Method 40 may include a step 43 of triggering AV valve closure.In some embodiments, step 43 may be performed by applying an excitatorycurrent to the at least one ventricle and/or by actuating an artificialvalve between the at least one atrium and the corresponding ventricle(s)to close. In some embodiments, step 41, step 42, and step 43 may berepeated as depicted by a return arrow leading back to step 41 from step43. In some embodiments, an excitatory current may be applied to bothventricles, at the same time or in sequence. In some embodiments, whereboth ventricles are paced in sequence, the time interval may be measuredbetween the onset of excitation of at least one atrium (e.g., the rightatrium) and the onset of excitation of the corresponding ventricle to bepaced (e.g., the right ventricle). In some embodiments, where the timeinterval is set to be zero or negative, step 43 may be performed beforeor at the same time as step 41. In some embodiments, the time intervalmay be measured in milliseconds.

Optionally, contraction of the atrium and the ventricle may be caused bycontrolling both contractions (e.g., by controlling the excitationsleading to the contractions). Optionally, the onset of excitation of theatrium is sensed, which sensing triggers the closing of a valve at theprescribed timing interval. Optionally, both atria are paced. In someembodiments, where both AV valves are closed in sequence (e.g., as bothventricles are paced in sequence), the timing interval is measured fromthe onset of excitation of the first atrium to be paced and the onset ofthe valve closing or the onset of excitation of at least one ventricle.Optionally the timing of an excitation (e.g., the onset of excitation)of one or more chambers is estimated, for example based on the timing inone or more preceding heart cycles, and one or more excitation stimuliare delivered to the same and/or to a different chamber at a desiredtime interval before and/or after the estimated timing.

In some embodiments, method 40 may be repeated for every heartbeat. Insome embodiments, method 40 may be performed intermittently. Forexample, the method may be applied once every few heartbeats.Alternatively, method 40 may be applied for a few heartbeats, stoppedfor one or more heartbeats, and then applied again. For example, method40 may be applied for 5 to 15 heartbeats, stopped for 2 to 5 heartbeats,and then resumed again. In some embodiments, the pattern ofapplication/avoiding application may be more complex and may beoptionally based on a predefined algorithm. For example, an algorithmmay adjust parameters of stimulation rather than simply stop and startstimulation. Application of method 40 in some embodiments reducesventricle filling between heartbeats thereby potentially reducing theejection profile. As used herein, the ejection profile of a heart is thetotal amount of blood pumped by the heart in a given period of time. Insome embodiments, an intermittent application of method 40 may beapplied to counteract a reduction in the ejection profile of the heart.

In some embodiments, the time interval applied in step 42 may beselected based on feedback. In such cases, method 40 may include step 44of sensing a feedback parameter from one or more of the heart chambers,any portion thereof, and/or the body of the patient. For example,feedback information may be obtained by monitoring directly orindirectly one or more of the atrial kick, blood pressure (e.g., at anartery), ventricular pressure, and/or atrial pressure. In someembodiments, feedback information may additionally or alternativelyinclude the degree of overlap between the time when the atrium contractsand the time when the AV valve is closed and/or the time when theventricle contracts. For example, an ultrasound sensor may be used todetect cardiac activity, for example, by ultrasound imaging of cardiacactivity or by creating an echocardiogram (ECHO). In some embodiments,step 44 may include using an ultrasound sensor to detect the flow ofblood (e.g., the velocity of flow) and/or cardiac tissue movement at anyarbitrary point using pulsed or continuous wave Doppler ultrasound.Optionally, step 44 may include using an ultrasound sensor to detect anA wave corresponding to the contraction of the left atrium and the flowof blood to the left ventricle.

Method may include a step 45 of adjusting the time interval from step 42based on the feedback information from step 44. For example, step 45 mayinclude adjusting the time interval based on a sensed blood pressure. Asshown by the arrow directed from step 45 to step 41 in FIG. 13, step 41,step 42, step 43, and/or step 44 may be repeated after performing step45. In some embodiments, the time interval may be initially set at afirst value during step 41 and, based on feedback sensing performedduring step 44, the time interval may be reduced or increased duringstep 45 until the feedback value is within a given range (or above orbelow a given value). For example, the time interval may be adjusteduntil such time that systolic blood pressure is above 100 mmHg and/orbelow 140 mmHg and/or diastolic blood pressure is below 90 mmHg and/orabove 60 mmHg.

In some embodiments, step 44 and step 45 may be performed duringoperation of method 40 for every application of step 43 (e.g.,application of a ventricular pacing stimulus). In some embodiments,alternatively or additionally, step 44 and step 45 may be performed uponproviding a device to a patient (e.g., by implantation of the device)according to one or more embodiments. The adjusting steps may berepeated periodically (for example by a care taker during a checkup)and/or intermittently (for example once an hour or once every fewapplications of a ventricular pacing stimulus). In some embodiments,step 45 may be performed when feedback information indicates that one ormore sensed parameters exceed a preset range for a period of time thatexceeds a predefined period.

The steps of method 40 may be performed in any order. For example, thesteps may be performed in the order indicated by the arrows shown inFIG. 13. In another embodiment, step 42 may be performed before step 41.

The timing of atrial contraction, atrial excitation, ventricularcontraction, closing and/or opening of the AV valve(s), and/or the flowor lack thereof of blood from one or more atria to the respectiveventricle(s) and/or blood pressure may be detected by any method knownin the art and may be used as feedback control. In some embodiments, theonset of excitation may be used as a trigger for the delivery of anexcitatory stimulus to one or more ventricles. The sensed informationmay be additionally or alternatively be used in the adjusting of atiming interval of the device.

Optionally, feedback parameters may allow responding to conditions thatrequire additional throughput from the heart, and rather than adjust thetiming interval they may be used to automatically stop the causing ofvalve closing at a shortened timing interval. For example, the feedbackparameters may lead to an adjustment during exercise. In this example, aheart rate sensor may be used to provide feedback information on theheart rate of the patient. If the heart rate is above a given thresholdthe feedback may be used to cause the device to stop. The device may beactivated again based on sensed feedback information, for example, whenthe heart rate is below a given threshold and/or after a predeterminedperiod has passed.

Embodiments of Devices for Reducing Blood Pressure

Attention is now drawn to FIG. 14, which schematically depicts anexemplary device 50 according to an embodiment. Device 50 may beconstructed and have components similar to a cardiac pacemakeressentially as known in the art with some modifications as discussedherein. Optionally, the device is implantable. Optionally, the devicecomprises components that may provide additional and/or alternativeelectrical treatments of the heart (e.g., defibrillation). Device 50 maybe configured for implantation in the body of a patient essentially asis known in the art for implantable pacemakers, optionally with somemodifications as discussed herein. Device 50 may include any componentsof system 700 and system 700 may include any components of device 50.

Device 50 may include a biocompatible body 51, one or more controllers52, a power source 53, and a telemetry unit 56. Body 51 may comprise ahousing for encasing a plurality of components of the device.Controller(s) 52 may be configured to control the operation of thedevice, and may implement any of the embodiments and methods disclosedherein. For example, controller(s) 52 may control the delivery ofstimulation pulses. In some embodiments, power source 53 may include abattery. For example, power source 53 may include a rechargeablebattery. In some embodiments, power source 53 may include a battery thatis rechargeable by induction. In some embodiments, telemetry unit 56 maybe configured to communicate with one or more other units and/orcomponents. For example, telemetry unit 56 may be configured tocommunicate with an external programmer and/or a receiving unit forreceiving data recorded on device 50 during operation.

In some embodiments, device 50 may be configured to be attached to oneor more electrodes and/or sensors. The electrodes and/or sensors may beintegrated in device 50, attached thereto, and/or connectable therewith.In some embodiments, the electrodes may include ventricular electrode(s)561 configured to pace at least one ventricle. Additionally oralternatively, the device may be connected, optionally via wires orwirelessly, to at least one implanted artificial valve 562.Additionally, device 50 may comprise one or more atrial electrode(s) 57for pacing one or more atria, and/or one or more atrial sensors 58 forsensing the onset of atrial excitation, and/or one or more sensors 59for providing other feedback parameters.

In some embodiments, sensor(s) 59 may comprise one or more pressuresensors, electrical sensors (e.g., ECG monitoring), flow sensors, heartrate sensors, activity sensors, and/or volume sensors. Sensor(s) 59 mayinclude mechanical sensors and/or electronic sensors (e.g., ultrasoundsensors, electrodes, and/or RF transceivers). In some embodiments,sensor(s) 59 may communicate with device 50 via telemetry.

In some embodiments, ventricular electrode(s) 561 and/or atrialelectrode(s) 57 may be standard pacing electrodes. Ventricularelectrode(s) 561 may be positioned relative to the heart at positions asknown in the art for ventricular pacing. For example, ventricularelectrode(s) may be placed in and/or near one or more of the ventricles.In some embodiments, atrial electrode(s) 57 may be placed in and/or nearone or more of the atria. In some embodiments, atrial electrode(s) 57may be attached to the one or more atria at one or more positionsselected to provide early detection of atrial excitation ordepolarization. For example, in some embodiments, atrial electrode(s) 57may be attached to the right atrium near the site of the sinoatrial (SA)node.

One position of ventricular electrode(s) 561 may be such that pacing mayreduce or minimize the prolongation of QRS when the heart is paced, toreduce or even minimize dyssynchrony. In some embodiments, this positionis on the ventricular septum near the Bundle of His. Ventricularelectrode(s) 561 may additionally or alternatively be placed on theepicardium of the heart or in coronary veins. More than one electrodecan be placed on the ventricles to provide biventricular pacing,optionally to reduce dyssynchrony.

Device 50 may include a pulse generator, or stimulation circuit,configured to deliver a stimulation pulse to at least one cardiacchamber. The pulse generator, or stimulation circuit, may include someor all standard capabilities of a conventional pacemaker. Controller 52may be configured to control the pulse generator, or stimulationcircuit. Atrial sensor(s) 58 (and optionally other electrode sensorsconfigured to sense other heart chambers) may be connected to device 50via specific circuits that will amplify the electrical activity of theheart and allow sampling and detection of the activation of the specificchamber. Other circuits may be configured to deliver stimulation to aspecific electrode to pace the heart, creating propagating electricalactivation.

In some embodiments, one or more additional sensors 59 may be placed inand/or on one or more of the atria and/or in and/or on one or more ofthe ventricles and/or in and/or on one or more other locations thatmight optionally be adjacent the heart. For example, one or more sensorsmay be placed on and/or in vena cava and/or on one or more arteriesand/or within one or more cardiac chambers. These sensors may measurepressure, or other indicators, such as, for example, impedance and/orflow.

In some embodiments, controller 52 may comprise or be a microprocessorpowered by power source 53. In some embodiments, device 50 may comprisea clock 54, for example, generated by a crystal. Device 50 may comprisean internal memory 55 and/or be connected to external memory. Forexample, device may connect to an external memory via telemetry unit 56.In some embodiments, telemetry unit 56 may be configured to allowcommunication with external devices such as a programmer and/or one ormore of sensors 59. Any and all feedback information and/or a log ofdevice operation may be stored in internal memory 55 and/or relayed bytelemetry unit 56 to an external memory unit.

In some embodiments, controller 52 may operate in accordance with atleast one embodiment of a method described herein.

In some embodiments, device 50 may comprise one or more sensors forsensing one or more feedback parameters to control the application ofthe AV delay and/or its magnitude.

Embodiments of Artificial Valves

Additionally or alternatively, device 50 may be configured to directlycontrol the operation of at least one implanted artificial valve 562.Attention is now drawn to FIG. 15, which schematically depicts anartificial valve 60 according to an embodiment of the invention. Valve60 as depicted in the example is a bi-leaflet, essentially as known inthe art for artificial valves. While the following example relates to abi-leaflet valve it is appreciated that embodiments may be implementedin other artificial valves, for example, caged ball valves and discvalves as well.

As shown in FIG. 15, valve 60 may comprise a ring 61 for suturing thevalve in place when implanted in a heart of a patient. Valve 60 mayinclude two semicircular leaflets 62 that rotate about struts 63attached to ring 61. In this schematic representation, other devicecomponents are schematically depicted as body 64, which corresponds tobody 51 as shown in FIG. 14. Body 64 may receive feedback informationfrom heart 65, in which valve 60 is implanted.

Valve 60 differs from conventional artificial valves in that its closuremay be directly controlled by device 50. Valve 60 may comprise amechanism (for example, a coil or a hydraulic mechanism) that isconfigured to actively cause closure of the valve (for example, byrotating struts 63 or by inflating a portion of the one or more ofleaflets 62). The mechanism may later be brought back to a relaxedposition to allow opening of the valve and to allow its repeated closingas needed. The relaxation may be performed at a predetermined time afterclosing. Additionally or alternatively, relaxation may be affected inresponse to a sensor reading ventricular activity (e.g., a pressuresensor). Control over valve 60 may be operated wirelessly (using atelemetry unit associated with the valve) or by wired communication withcomponents in body 64. In some embodiments, valve 60 may be a valveconfigured to be opened and closed independent of fluid pressure actingon the valve. For example, valve 60 may be a ball valve.

Effects of Embodiments for Reducing Blood Pressure

Overall, some embodiments of the disclosed methods and systems providedifferent approaches to reducing the filling of at least one ventricle,consequently reducing blood pressure. Unlike previous mechanical methodsfor reducing blood pressure, some embodiments described herein mayachieve this goal without increasing pressure within the at least onecorresponding atrium. Without an increase in atrial pressure to triggerthe secretion of atrial natriuretic hormone, or atrial natriureticpeptide, the reduction of blood pressure can be mechanically controlled.The disclosed embodiments may prevent an unwanted effect on heart rateand may reduce the likelihood of canon atrial waves.

Some of the disclosed embodiments may reduce atrial kick while alsoincreasing atrial stretch, causing the release of atrial natriureticpeptide. For example, disclosed embodiments may comprise a methodincluding a step of stimulating a heart to cause an atrium thereof tocontract while a heart valve associated with the atrium is closed suchthat the contraction distends the atrium. Some embodiments, as describedabove, may increase atrial pressure and atrial stretch by using cardiacstimulation that reaches maximum atrial pressure resulting from atrialcontraction at a period of time overlapping maximum passive increase inatrial pressure, to cause secretion of atrial natriuretic hormone oratrial natriuretic peptide, which may reduce blood pressure aredescribed above. Some embodiments, as described above, may increaseatrial pressure and atrial stretch by using cardiac stimulationconfigured to have an atrium contract such that an atrial pressureresulting from atrial contraction of an atrium overlaps in time apassive pressure build-up of the atrium, thereby providing an atrialpressure of the atrium that is a combination of the atrial pressureresulting from atrial contraction and the passive pressure build-up andis higher than an atrial pressure of the atrium would be without thestimulation, thereby causing increased atrial stretch of the atrium thatreduces blood pressure through hormonal or neuronal pathways. Reducingatrial kick and causing the release of atrial natriuretic peptide at thesame time may have a synergistic effect on lowering blood pressure. Insome embodiments, controlling the timing of valve closure relative toatrial contraction may control the amount one or more atria stretches.

Unlike previous pharmaceutical or mechanical methods for reducing bloodpressure, some of the disclosed embodiments achieve the goal of reducingblood pressure immediately. For example, a reduction in blood pressuremay occur within 1-3 sec or within 1, 3, or 5 heartbeats of theapplication of electricity and the blood pressure may reach a minimalblood pressure value within less than 5 heartbeats from the beginning ofstimulation.

Examples discussed above strike a balance between mechanical treatment,neuronal feedback, and the natural release of hormones that causeadaptation. The mechanical treatment and the natural release of hormonesmay be additive or even synergistic mechanisms. The hormonal releaseaffects the cardiovascular system while the mechanical treatment affectsthe heart itself. Intermittently delivering the mechanical treatment toreduce blood pressure may affect both the neuronal and hormonal feedbackcontrolling the cardiovascular system and reduce adaptation.

The headings used in this specification are only meant to aid inorganization and do not define any terms.

The present disclosure is related to the following applications, all ofwhich are herein incorporated by reference in their entirety:

-   -   U.S. Patent Application Publication Number 2012/0215272 to Levin        et al., published on Aug. 23, 2012, now U.S. Pat. No. 8,521,280,        issued Aug. 27, 2013;    -   U.S. Patent Application Publication Number 2011/0172731 to Levin        et al., published on Jul. 14, 2011, now U.S. Pat. No. 8,515,536,        issued Aug. 20, 2013;    -   U.S. Patent Application Publication Number 2013/0331901 to Levin        et al., published on Dec. 12, 2013; and    -   U.S. Patent Application Publication Number 2012/0041502 to        Schwartz et al., published on Feb. 16, 2012, now U.S. Pat. No.        8,428,729, issued Apr. 23, 2013.

While various embodiments of the invention have been described, thedescription is intended to be exemplary, rather than limiting and itwill be apparent to those of ordinary skill in the art that many moreembodiments and implementations are possible that are within the scopeof the invention. Accordingly, the invention is not to be restrictedexcept in light of the attached claims and their equivalents. Also,various modifications and changes may be made within the scope of theattached claims.

What is claimed is:
 1. A system for reducing blood pressure in apatient, the system comprising: a stimulation circuit configured todeliver a stimulation pulse to at least one cardiac chamber of a heartof the patient; and at least one controller configured to executedelivery of one or more stimulation patterns of stimulation pulses tothe at least one cardiac chamber, wherein at least one of thestimulation pulses stimulates the heart to cause increased atrialstretch of a wall of an atrium as a result of timing of atrialcontraction and ventricular contraction, and wherein the increasedatrial stretch is higher than an atrial stretch would be without thestimulation, such that the blood pressure of the patient is reduced. 2.The system of claim 1, wherein the increased atrial stretch reducesblood pressure through at least one of hormonal pathways or neuralpathways.
 3. The system of claim 1, wherein, to cause the increasedatrial stretch, the at least one of the stimulation pulses stimulatesthe heart such that the atrium contracts when pressure in a ventricle ofthe heart is about maximal so that active force of the atrialcontraction increases atrial stretch above maximal passive atrialstretch caused by the ventricular contraction.
 4. The system of claim 1,wherein, to cause the increased atrial stretch, the at least one of thestimulation pulses stimulates a ventricle of the heart to cause theventricle to commence contraction at such timing that peak atrialcontraction occurs when the ventricle is near or at maximal stretch. 5.The system of claim 1, wherein the at least one controller is configuredto determine atrial stretch by measuring changes in dimension of theatrium.
 6. The system of claim 1, wherein, to cause the increased atrialstretch, the at least one of the stimulation pulses stimulates the heartto control timing of valve closure relative to atrial contraction. 7.The system of claim 1, wherein the controller is configured to deliverthe one or more stimulation patterns for a predetermined time interval,and to cause the increased atrial stretch to occur for a portion of thepredetermined time interval.
 8. The system of claim 1, wherein theincreased atrial stretch occurs transiently during the stimulation. 9.The system of claim 1, wherein, to cause the increased atrial stretch,the at least one of the stimulation pulses stimulates the heart suchthat an atrial stretch resulting from atrial contraction overlaps intime a passive atrial stretch.
 10. The system of claim 9, wherein thepassive atrial stretch occurs during isovolumic contraction of aventricle of the heart.
 11. The system of claim 9, wherein the passiveatrial stretch occurs during a rapid ejection phase of a ventricle ofthe heart.
 12. The system of claim 1, wherein, to cause the increasedatrial stretch, the at least one of the stimulation pulses stimulatesthe heart such that a maximum of atrial pressure resulting from atrialcontraction overlaps in time a maximum passive atrial stretch.
 13. Thesystem of claim 12, wherein the maximum passive atrial stretch occurs ata time between about 25 ms after start of an isovolumic phase and about10 ms after end of the isovolumic phase.
 14. The system of claim 12,wherein the maximum passive atrial stretch occurs between a start of asecond half of an isovolumic phase and a first approximately 10 ms of arapid ejection phase.
 15. The system of claim 1, wherein the one or morestimulation patterns comprise pacing the atrium and a ventricle of theheart at a substantially equal rate.
 16. The system of claim 1, whereinthe one or more stimulation patterns comprise pacing the atrium at arate higher than a rate at which a ventricle of the heart is paced. 17.The system of claim 1, wherein the at least one of the stimulationpulses comprises stimulating the atrium of the heart such that theatrium contracts only once during a single cardiac cycle.
 18. The systemof claim 1, wherein the timing corresponds to an atrioventricular delayof between approximately 60 ms and approximately 0 ms.
 19. A method,carried out with an implanted heart muscle stimulator associated with aheart of a patient, for reducing blood pressure of the patient, themethod comprising: delivering one or more stimulation patterns ofstimulation pulses to at least one cardiac chamber of the heart of thepatient; and stimulating the heart with at least one of the stimulationpulses to cause increased atrial stretch of a wall of an atrium as aresult of timing of atrial contraction and ventricular contraction,wherein the increased atrial stretch is higher than an atrial stretchwould be without the stimulation, such that the blood pressure of thepatient is reduced.
 20. The method of claim 19, wherein, to cause theincreased atrial stretch, the at least one of the stimulation pulsesstimulates the heart such that the atrium contracts when pressure in aventricle of the heart is about maximal so that active force of theatrial contraction increases atrial stretch above maximal passive atrialstretch caused by the ventricular contraction.
 21. A system for reducingblood pressure in a patient, the system comprising: a stimulationcircuit configured to deliver a stimulation pulse to at least onecardiac chamber of a heart of the patient; and at least one controllerconfigured to execute delivery of one or more stimulation patterns ofstimulation pulses to the at least one cardiac chamber, wherein at leastone of the stimulation pulses stimulates the heart to provide a timingof atrial contraction and ventricle contraction that increases atrialstretch, and wherein the increased atrial stretch is higher than anatrial stretch would be without the stimulation, such that the bloodpressure of the patient is reduced.
 22. The system of claim 21, whereinthe at least one of the stimulation pulses stimulates the heart suchthat a maximum of atrial stretch resulting from atrial contractionoverlaps in time a maximum passive atrial stretch.